Process for the preparation of imidazopyridine derivatives

ABSTRACT

The present invention provides an industrially advantageous process for preparing a 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative represented by the following formula (II) which is a precursor of an antagonist against an angiotensin II receptor useful as an antihypertensive drug, a biphenyl derivative which is a precursor of the substituent of the pyridine derivative, a process for the preparation thereof, and an intermediate useful for the preparation of the biphenyl derivative: ##STR1##

This application is a 371 of PCT/JP93/01776 filed Dec. 7, 1993.

DETAILED DESCRIPTION OF THE INVENTION

1. Field of Industrial Application

The present invention relates to a process for the preparation of a2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative(II) which is disclosed in, e.g., Japanese Patent Publication-A Nos.3-95181 (and European Patent Publication-A No. 420237 correspondingthereof) and 3-236377 and is a precursor of an antagonist againstangiotensin II receptor useful as an antihypertensive drug and a remedyfor hemal lesions, and an intermediate useful for the preparationthereof.

The present invention relates to a process for the preparation of a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II) which is disclosed in, e.g., Japanese PatentPublication-A Nos. 3-5480, 3-95181, 3-188076 (and European PatentPublication-A No. 426021 corresponding thereof) and 3-236377 (andEuropean Patent Publication-A No. 420237 corresponding thereof), andJapanese Patent Application No. 4-328986 and is a precursor of anantagonist against angiotensin II receptor useful as an antihypertensivedrug and a remedy for hemal lesions, and an intermediate useful for thepreparation thereof.

The present invention relates to a biphenyloxazoline derivative (I)useful as an intermediate for the preparation of a medicine, a processfor the preparation thereof, and an intermediate useful for thepreparation thereof. More particularly, the present invention relates toa biphenyloxazoline derivative (I) that is a precursor for thesubstituent of the antagonist against angiotensin II receptor which isdisclosed in, e.g., Japanese Patent Publication-A Nos. 3-95181 and3-236377 (and European Patent Publication-A No. 420237 correspondingthereof) and Japanese Patent Application No. 4-328986 and is useful asan antihypertensive drug and a remedy for hemal lesions, a process forthe preparation thereof, and an intermediate useful for the preparationthereof.

The present invention relates to a sulfonyloxybiphenylcarboxylic esterderivative (I) useful as an intermediate for the preparation of amedicine, a process for the preparation thereof, and an intermediateuseful for the preparation thereof. More particularly, the presentinvention relates to a sulfonyloxy-biphenylcarboxylic ester derivative(I) that is a precursor for the substituent of the antagonist againstangiotensin II receptor which is disclosed in, e.g., Japanese PatentPublication-A Nos. 3-95181 and 3-236377 (and European PatentPublication-A No. 420237 corresponding thereof) and Japanese PatentApplication No. 4-328986 and is useful as an antihypertensive drug and aremedy for hemal lesions, a process for the preparation thereof, and anintermediate useful for the preparation thereof.

The present invention relates to a process for the preparation of ahalomethyl-biphenylcarboxylic ester derivative (II) useful as anintermediate for the preparation of a medicine. More particularly, thepresent invention relates to a process for the preparation of ahalomethyl-biphenylcarboxylic ester derivative (II) that is a precursorfor the substituent of the antagonist against angiotensin II receptorwhich is disclosed in, e.g., Japanese Patent Publication-A Nos. 3-95181and 3-236377 (and European Patent Publication-A No. 420237 correspondingthereof) and Japanese Patent Application No. 4-328986 and is useful asan antihypertensive drug and a remedy for hemal lesions.

2. Prior Art

As described in the Japanese Patent Publication-A No. 3-236377, a2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative(II) has hitherto been prepared mainly by a process which comprisesnitrating a 2-aminopyridine derivative into a 2-amino-3-nitropyridinederivative, reducing it to form a 2,3-diaminopyridine derivative,conducting the N-acylation and cyclization thereof simultaneously toform a 3H-imidazo[4,5-b]pyridine ring and finally conducting theN-alkylation thereof. This preparation process of the prior art can berepresented by the following reaction formula (reaction scheme-1):##STR2##

As a process for conducting the N-alkylation for preparing the objectivecompound in the above process, for example, the Japanese PatentPublication-A No. 3-236377 discloses a process which comprises reactingthe 3H-imidazo[4,5-b]pyridine derivative with an N-alkylating reagent ina solvent such as N,N-dimethylformamide, dimethyl sulfoxide,acetonitrile and acetone in the presence of a base such as sodiumhydride, sodium methoxide, potassium t-butoxide, sodium carbonate orpotassium carbonate to form a2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative(II). Further, Japanese Patent Publication-A Nos. 63-23868, 3-5480 and3-95181 also disclose processes wherein a3-(2'-alkoxycarbonylbiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative or an N-[(2'-alkoxycarbonylbiphenyl-4-yl)methyl]imidazolederivative is prepared through the N-alkylation of an imidazole ring ina similar manner to that described above.

As described in the Japanese Patent Publication-A No. 3-236377, a2-alkyl-3-(2'-cyanobiphenyl-4-yl)-methyl-3H-imidazo[4,5-b]pyridinederivative (II) has hitherto been prepared mainly by a process whichcomprises nitrating a 2-aminopyridine derivative into a2-amino-3-nitropyridine derivative, reducing it to form a2,3-diaminopyridine derivative, conducting the N-acylation andcyclization thereof simultaneously to form a 3H-imidazo[4,5-b]pyridinering and finally conducting the N-alkylation thereof. This preparationprocess of the prior art can be represented by the following reactionformula (reaction scheme-2): ##STR3##

As a process for conducting the N-alkylation for preparing the objectivecompound in the above process, for example, the Japanese PatentPublication-A No. 3-236377 discloses a process which comprises reactingthe 3H-imidazo[4,5-b]pyridine derivative with an N-alkylating reagent ina solvent such as N,N-dimethylformamide, dimethyl sulfoxide,acetonitrile and acetone in the presence of a base such as sodiumhydride, sodium methoxide, potassium t-butoxide, sodium carbonate orpotassium carbonate to form a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II). Further, Japanese Patent Publication-A Nos. 3-5480,3-95181 and 3-188076 also disclose processes wherein a3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative isprepared through the N-alkylation of an imidazole ring in a similarmanner to that described above.

As described in, e.g., Japanese Patent Publication-A No. 3-236377, ithas been a practice in the prior art to form the side chain of biphenylof a2-alkyl-3-(2'-alkoxycarbonylbiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative which is an antagonist against angiotensin II receptor by amethod wherein the N-alkylation is conducted with a4'-bromomethyl-2-biphenylcarboxylic ester.

Such a 4'-bromomethyl-2-biphenylcarboxylic ester is prepared by aprocess which comprises preparing 4'-methyl-2-biphenyloxazoline in amanner described in Journal of Organic Chemistry (J. Org. Chem.), 43(7),1372 to 1379, 1978, then hydrolyzing it into4'-methyl-2-biphenylcarboxylic acid, then esterifying it into a4'-methyl-2-biphenylcarboxylic ester, and, further, brominating it in amanner disclosed in the Japanese Patent Publication-A No. 63-23868. Thispreparation process is represented hereinafter (reaction scheme-3):##STR4##

Problem to be Solved by the Invention

The process for the preparation of an imidazo[4,5-b]pyridine derivativeaccording to the prior art begins with the step of nitrating a2-aminopyridine derivative into a 2-amino-3-nitropyridine derivative.However, the nitration step is disadvantageous. That is, a2-aminopyridine derivative exhibits an ortho, para directivity innitration, so that the nitration gives not only an objective2-amino-3-nitropyridine derivative which is a product of thesubstitution ortho to the amino group, but also a2-amino-5-nitropyridine derivative which is a product of thesubstitution para to it as a by-product. Futher, the proportion of theundesired 5-nitro derivative is as overwhelmingly high as about 80 to90%, while that of the objective derivative is as low as about 10 to 20%(see the above reaction schemes 1 and 2).

The above process of the prior art involves the step of conducting theN-alkylation of the NH group of the imidazole ring after formingimidazo[4,5-b]pyridine ring. The N-alkylation step is also problematicin that the isomerization of the imidazopyridine ring is caused to givenot only the objective 3-alkyl-3H-imidazo[4,5-b]pyridine derivative, butalso a 1-alkyl-1H-imidazo[4,5-b]pyridine derivative and a4-alkyl-4H-imidazo[4,5-b]pyridine derivative as by-products because theimidazo[4,5-b]pyridine ring loses the hydrogen atom owing to theabstraction by a base to result in a transition state wherein electronis delocalized. The yield of the objective compound is as low as about20 to 40%, also in this reaction (see the above reaction schemes 1 and2).

As described above, the process for the preparation of imidazopyridinesaccording to the prior art involves two stages problematic in yieldremarkably before obtaining the objective compound, so that the processis uneconomical and takes much labor in separation and purification,being not always satisfactory as an industrial process. Under thesecircumstances, it has been expected to develop an industriallyadvantageous process by which an objective imidazopyridine derivativecan be prepared from a starting 2-aminopyridine derivative in a highyield.

Further, as described in, for example, the Japanese Patent Publication-ANo. 3-236377, it has been a practice in the prior art to form thebiphenyl moiety of a2-alkyl-3-(2'-alkoxycarbonylbiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative by the N-alkylation with a 2-(4'-bromomethylphenyl)benzoicacid ester. However, the preparation of the2-(4'-bromomethylphenyl)benzoic acid ester according to the processdisclosed in the Japanese Patent Publication-A No. 63-23868 has thedisadvantage that it is not suitable for an industrial productionthereof because the N-bromosuccinimide, which is used for thebromination is expensive and the bromination is a free-radical reactionand therefore is too rapid to be controlled.

Furthermore, a 2-(4'-bromomethylphenyl)benzoic acid ester has a highactivity to react easily, but it could not be stored stably because ofthe high activity, so that it had to be prepared immediately before theuse and was extremely poor in workability. Furthermore, owing to thehigh activity, the ester has a disadvantage of being liable to causedecomposition or a side reaction in the reaction, so that the obtainedN-alkylation product had a low purity and was contaminated with manyby-products to result in difficult purification. Under thesecircumstances, it has also been expected to find a novel imidazopyridinederivative which is prepared by using, as an N-alkylating agent, anactive biphenyl derivative (IV) which is excellent in reactivity andoperability and gives a high-purity product.

Further, with the purpose of solving the above problem, the JapanesePatent Publication-A No. 5-95181 discloses a process which comprisesconducting the N-acylation and cyclization of starting5-bromo-4-methyl-2,3-diaminopyridine simultaneously to form6-bromo-2-butyl-7-methyl-3H- imidazo[4,5-b]pyridine and treating it withn-butyllithium and methanol successively to form2-butyl-7-methyl-3H-imidazo[4,5-b]pyridine. Although this process couldgive the objective compound in a high yield, the process wasinsufficient as an industrial one because it uses n-butyllithium whichis very dangerous owing to its high ignitability and is expensive,necessitates the preparation of an anhydrous solvent prior to thereaction and requires specialized production facilities for maintainingthe anhydrous state.

Furthermore, the Japanese Patent Publication-A No. 3-188076 discloses aprocess for preparing2-butyl-8-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridineby reacting a2-[N-(2'-cyanobiphenyl-4-yl)methyl-N-valeryl]amino-5-bromo-4-methyl-3-nitropyridinewith iron in acetic acid. However, this patent document is silent on themeans of dehalogenation. Accordingly, it was impossible to prepare the3-alkyl-3H-imidazo[4,5-b]pyridine derivative which is a precursor of anantagonist against angiotensin II receptor and which corresponds to acompound prepared by replacing the 6-position bromine atom of the aboveimidazopyridine by a hydrogen atom.

Under these circumstances, it has been expected to develop anindustrially advantageous process for preparing a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II) from a 2-amino-5-halogeno-4-methyl-3-nitropyridinederivative (I) with safety in a high yield.

The 4'-bromomethyl-2-biphenylcarboxylic ester which has hitherto beenused has a high activity to react easily, but it could not be storedbecause it was poor in stability due to its high activity. Therefore, ithad been prepared immediately before the use and was extremely poor inworkability. Further, due to the high activity, the ester also has adisadvantage of being liable to cause decomposition or a side reactionin:the reaction, so that the obtained N-alkylation product had a lowpurity and the by-products were varied to result in difficultpurification. Furthermore, all of the processes disclosed in the priorart failed in the preparation of a 4'-chloromethyl-2-biphenylcarboxylicester exhibiting a desirable reactivity in the N-alkylation.

Further, N-bromosuccinimide has been used for the bromination in thepreparation of the 4'-bromomethyl-2-biphenylcarboxylic ester accordingto the process disclosed in the Japanese Patent Publication-A No.63-23868. However, there has been a disadvantage that it is unsuitablefor the industrial production thereof because this reagent is expensiveand the bromination is a free-radical reaction and therefore is toorapid to be controlled.

Further, the 4'-bromomethyl-2-biphenylcarboxylic ester which hashitherto been used has a high activity to react easily, but it could notbe stored because it was poor in stability due to its high activity.Therefore, it had been prepared immediately before the use and wasextremely poor in workability. Furthermore, due to the high activity,the ester also has a disadvantage of being liable to cause decompositionor a side reaction in the reaction, so that the obtained N-alkylationproduct had a low purity and the by-products were varied to result indifficult purification. Under these circumstances, an active4'-chloromethyl-2-biphenylcarboxylic ester and the like excellent inoperatability have also been expected, but the process disclosed in theJapanese Patent Publication-A No. 63-28868 failed in the preparationthereof.

As described above, the 4'-bromomethyl-2-biphenylcarboxylic ester whichhas hitherto been used took much labor to separate and purify theN-alkylation product and had disadvantages in economic efficiency andsafeness, in addition to its poor working efficiency as an intermediate.Thus, the ester was not always satisfactory as an intermediate forindustrial production.

Under these circumstances, an industrially advantageous active biphenylintermediate with which the imidazopyridine derivative useful as anantagonist against angiotensin II receptor can be prepared safely in ahigh yield at a high purity and a high economic efficiency has beenexpected. Additionally, an industrially advantageous process forpreparing a halomethyl-biphenylcarboxylic ester derivative (such as a4'-chloromethyl-2-biphenylcarboxylic ester) with which theimidazopyridine derivative useful as an antagonist against angiotensinII receptor can be prepared safely in a high yield at a high purity anda high economic efficiency and which has a desirable activity.

Description of the Invention

The present inventors have extensively studied with top priority beinggiven to an improvement in the yield of the N-alkylation and also withthe purpose of improving the nitration step, because, in the productionof an imidazopyridine derivative as an objective compound, lower theyield of a step near the final one in a process, less efficious theprocess as an industrial one. As a result, they have found that theabove objects can be attained and a2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative(II) can be produced by converting a 2-amino-3-nitropyridine derivative(V) into a 2-[N-(biphenyl-4-yl)methyl]-alkylamido-3-nitropyridinederivative (I) through amidation followed by N-alkylation and conductingthe cyclization thereof under reducing conditions. The present inventionhas been accomplished on the basis of this finding.

Meanwhile, it is known that a 2-amino-5-bromopyridine derivative or2-amino-5-chloropyridine derivative can be prepared from a2-aminopyridine derivative by bromination or chlorination in a highyield [see Journal of American Chemical Society (J.A.C.S.), 79, 6421 to6426, 1957, Journal of Organic Chemistry (J. Org. Chem.), 24, 1455 to1460, 1959 and so forth]. The present inventors have also found thatsuch a 2-amino-5-halogenopyridine derivative as a starting material canbe selectively nitrated into a 3-nitro derivative by virtue of thepresence of a halogen atom at the 5-position of the derivative, by whichthe problem of the nitration process according to the prior art can besolved.

Further, the present invention is advantageous that no particular stepis necessitated for eliminating the halogen atom introduced at the5-position as a protecting group against nitration because the halogenatom at the 5-position can be eliminated and replaced by a hydrogen atomsimultaneously with the reductive cyclization of the final step.Accordingly, the process of the present invention is industriallyadvantageous.

Further, the present inventors have also found that the objectiveimidazopyridine derivative can be prepared at high purity with excellentoperability by using an active biphenyl derivative (IV), examples ofwhich include not only 2-(4'-bromomethylphenyl)benzoic acid esters whichhave hitherto been used, but also 2-(4'-chloromethylphenyl)benzoic acidesters, 2-(4'-alkylsulfonyloxymethylphenyl)benzoic acid esterderivatives, 2-(4'-arylsulfonyloxymethylphenyl)benzoic acid esterderivatives, 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline,4,4-dimethyl-2-(4'-halomethyl-biphenyl-2-yl)oxazoline derivatives,4,4-dimethyl-2-(4'-alkylsulfonyloxymethyl-biphenyl-2-yl)oxazolinederivatives and4,4-dimethyl-2-(4'-arylsulfonyloxymethyl-biphenyl-2-yl)oxazolinederivatives, and has been accomplished the present invention. Theoutline of the reaction path according to the present invention isrepresented by the following chemical reaction formula (reactionscheme-4): ##STR5##

Accordingly, an object of the present invention is to provide anindustrially advantageous process for the preparation of a2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative(II) which is a precursor of an antagonist against an angiotensin IIreceptor useful as an antihypertensive drug or a remedy for hemallesions.

Then, the 2-[N-(biphenyl-4-yl)methyl]alkylamido-3-nitropyridinederivative (I) according to the present invention has the followingchemical structural formula: ##STR6## wherein R¹ represents a hydrogenatom or a halogen atom, with the proviso that the halogen atom is abromine atom or a chlorine atom; R² represents a hydrogen atom or amethyl group; R³ represents a cycloalkyl group, a lower alkyl group or alower alkoxy group; and R⁴ represents a group represented by thefollowing general formula:

    --COOR.sup.5

[wherein R⁵ represents a lower alkyl group, a cycloalkyl group, analkoxyalkyl group, a thioalkoxyalkyl group, a cycloether group, an arylgroup, an aralkyl group, an alkenyl group, an alkynyl group or atrialkylsilyl group] or a group represented by the following generalformula: ##STR7##

Specific examples of R³ include cycloalkyl groups such as a cyclopropylgroup, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group;lower alkyl groups such as alkyl groups having 1 to 6 carbon atoms,e.g., a methyl group, an ethyl group, a n-propyl group, an i-propylgroup, a n-butyl group, an i-butyl group, a t-butyl group, an amyl groupand a hexyl group; and lower alkoxy groups such as lower alkoxy groupshaving 1 to 6 carbon atoms, e.g., a methoxy group, an ethoxy group, an-propoxy group, an i-propoxy group, a butoxy group, a pentyloxy groupand a hexyloxy group.

Specific examples of R⁵ include lower alkyl groups such as alkyl groupshaving 1 to 10 carbon atoms, e.g., a methyl group, an ethyl group, an-propyl group, an i-propyl group, a n-butyl group, an i-butyl group, at-butyl group, a n-pentyl group, an i-pentyl group, a t-pentyl group, ahexyl group, an octyl group and a decyl group; cycloalkyl groups such asa cyclopropyl group, a cyclobutyl group, a cyclopentyl group and acyclohexyl group; alkoxyalkyl groups such as a methoxymethyl group, anethoxymethyl group, a methoxyethyl group, an ethoxyethyl group, amethoxyethoxymethyl group, a phenoxymethyl group and a benzyloxymethylgroup; thioalkoxyalkyl groups such as a methylthiomethyl group, amethylthioethyl group, an ethylthiomethyl group, a phenylthiomethylgroup and a benzylthiomethyl group; cycloether groups such as atetrahydropyranyl group and a tetrahydrofuranyl group; aryl groups suchas a phenyl group, a tolyl group and a xylyl group; aralkyl groups suchas a benzyl group, a phenethyl group, a methylbenzyl group, atrimethylbenzyl group, a nitrobenzyl group and a phenacyl group; alkenylgroups such as an allyl group, a propenyl group and a cinnamyl group;alkynyl groups such as a propargyl group; and trialkylsilyl groups suchas a trimethylsilyl group, a triethylsilyl group, t-butyldimethylsilylgroup, an i-propyldimethylsilyl group and a phenyldimethylsilyl group.Among them, preferable ones include lower alkyl groups having 1 to 6carbon atoms, a cycloalkyl group, a methoxymethyl group, atetrahydropyranyl group, a phenyl group, a benzyl group and atrimethylsilyl group.

Further, specific and representative examples of the2-[N-(biphenyl-4-yl)methyl]alkylamido-3-nitropyridine derivative (I)according to the present invention include, for example, the followingcompounds, though the derivative (I) is not limited to them.

(1)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-4-methyl-3-nitropyridine

(2)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-4,6-dimethyl-3-nitropyridine

(3)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine

(4)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-chloro-4-methyl-3-nitropyridine

(5)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]-cyclopropanecarboxamido-5-bromo-4,6-dimethyl-3-nitropyridine

(6)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-chloro-4,6-dimethyl-3-nitropyridine

(7)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]butyrylamino-4-methyl-3-nitropyridine

(8)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]butyrylamino-4,6-dimethyl-3-nitropyridine

(9)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]butyrylamino-5-bromo-4-methyl-3-nitropyridine

(10)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]butyrylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(11)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]valerylamino-4-methyl-3-nitropyridine

(12)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]valerylamino-4,6-dimethyl-3-nitropyridine

(13)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]valerylamino-5-bromo-4-methyl-3-nitropyridine

(14)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]valerylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(15) 2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-4-methyl-3-nitropyridine

(16)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-4,6-dimethyl-3nitropyridine

(17)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine

(18)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-5-chloro-4-methyl-3-nitropyridine

(19)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-5-bromo-4,6-dimethyl-3-nitropyridine

(20)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-5-chloro-4,6-dimethyl-3-nitropyridine

(21)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]butyrylamino-4-methyl-3-nitropyridine

(22)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]butyrylamino-4,6-dimethyl-3-nitropyridine

(23)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]butyrylamino-5-bromo-4-methyl-3-nitropyridine

(24)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]butyrylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(25)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]valerylamino-4-methyl-3-nitropyridine

(26)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]valerylamino-4,6-dimethyl-3-nitropyridine

(27)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]valerylamino-5-bromo-4-methyl-3-nitropyridine

(28)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]valerylamino-5-bromo-4,6-dimethyl-3-nitropyridine

The 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative(II) according to the present invention is represented by the followingstructural formula: ##STR8##

In the formula, R² R³ and R⁴ are each as defined above. Specific andrepresentative examples of the2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative(II) according to the present invention include, for example, thefollowing compounds, though the derivative (II) is not limited to them.

(1)2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

(2)2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(3)2-n-propyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

(4)2-n-propyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(5)2-n-butyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

(6)2-n-butyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(7)2-ethyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

(8)2-ethyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-5,V-dimethyl-3H-imidazo[4,5-b]pyridine

(9)2-cyclopropyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-7-methyl-3H-imidazo[4,5-b]pyridine

(10)2-cyclopropyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(11)2-n-propyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-7-methyl-3H-imidazo[4,5-b]pyridine

(12)2-n-propyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(13)2-n-butyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-7-methyl-3H-imidazo[4,5-b]pyridine

(14)2-n-butyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(15)2-ethyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-7-methyl-3H-imidazo[4,5-b]pyridine

(16)2-ethyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The 2-alkylamido-3-nitropyridine derivative (III) obtained in step 1 isrepresented by the following chemical structural formula: ##STR9##

In the formula, R¹, R² and R³ and each as defined above. Further,specific examples of the 2-alkyl-amido-3-nitropyridine derivative (III)according to the present invention include the following compounds,though the derivative (III) is not limited to them.

(1) 2-cyclopropanecarboxamido-4-methyl-3-nitropyridine

(2) 2-cyclopropanecarboxamido-4,6-dimethyl-3-nitropyridine

(3) 2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine

(4) 2-cyclopropanecarboxamido-5-chloro-4-methyl-3-nitropyridine

(5) 2-cyclopropanecarboxamido-5-bromo-4,6-dimethyl-3-nitropyridine

(6) 2-cyclopropanecarboxamido-5-chloro-4,6-dimethyl-3-nitropyridine

(7) 2-butyrylamino-4-methyl-3-nitropyridine

(8) 2-butyrylamino-4,6-dimethyl-3-nitropyridine

(9) 2-butyrylamino-5-bromo-4-methyl-3-nitropyridine

(10) 2-butyrylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(11) 2-valerylamino-4-methyl-3-nitropyridine

(12) 2-valerylamino-4,6-dimethyl-3-nitropyridine

(13) 2-valerylamino-5-bromo-4-methyl-3-nitropyridine

(14) 2-valerylamino-5-bromo-4,6-dimethyl-3-nitropyridine

The active biphenyl derivative (IV) according to the present inventionis represented by the following general formula: ##STR10##

In the formula, Y represents a leaving group in the course of organicsynthesis, preferably a hydroxyl group, a halogen atom, a loweralkylsulfonyl-oxy group; or an arylsulfonyloxy group; and R⁴ is asdefined above. Specific examples of the halogen atom include a chlorineatom, a bromine atom, an iodine atom and a fluorine atom; those of thelower alkyl-sulfonyloxy group include groups having a lower alkyl groupof 1 to 6 carbon atoms in the molecule, such as a methanesulfonyloxygroup and an ethanesulfonyloxy group; and those of the arylsulfonyloxygroup include a bezenesulfonyloxy group and a p-toluenesulfonyloxygroup. Furthermore, specific examples of the active biphenyl derivative(IV) according to the present invention include the following compounds,though the derivative (IV) is not limited to them. These compounds canbe prepared by the process disclosed in the Japanese PatentPublication-A No. 3-236377 and the processes described hereinafter.

(1) methyl 2-(4'-hydroxymethylphenyl)benzoate

(2) methyl 3-(4'-hydroxymethylphenyl)benzoate

(3) methyl 4-(4'-hydroxymethylphenyl)benzoate

(4) ethyl 2-(4'-hydroxymethylphenyl)benzoate

(5) ethyl 3-(4'-hydroxymethylphenyl)benzoate

(6) ethyl 4-(4'-hydroxymethylphenyl)benzoate

(7) propyl 2-(4'-hydroxymethylphenyl)benzoate

(8) butyl 2-(4'-hydroxymethylphenyl)benzoate

(9) phenyl 2-(4'-hydroxymethylphenyl)benzoate

(10) benzyl 2-(4'-hydroxymethylphenyl)benzoate

(11) tetrahydropyranyl 2-(4'-hydroxymethylphenyl)benzoate

(12) tetrahydrofuranyl 2-(4'-hydroxymethylphenyl)benzoate

(13) trimethylsilyl 2-(4'-hydroxymethylphenyl)benzoate

(14) methoxymethyl 2-(4'-hydroxymethylphenyl)benzoate

(15) thiomethoxymethyl 2-(4'-hydroxymethylphenyl)benzoate

(16) methyl 2-(4'-bromomethylphenyl)benzoate

(17) methyl 3-(4'-bromomethylphenyl)benzoate

(18) methyl 4-(4'-bromomethylphenyl)benzoate

(19) methyl 2-(4'-chloromethylphenyl)benzoate

(20) methyl 3-(4'-chloromethylphenyl)benzoate

(21) methyl 4-(4'-chloromethylphenyl)benzoate

(22) methyl 2-(4'-methanesulfonyloxymethylphenylbenzoate

(23) methyl 3-(4'-methanesulfonyloxymethylphenyl)benzoate

(24) methyl 4-(4'-methanesulfonyloxymethylphenyl)benzoate

(25) ethyl 2-(4'-methanesulfonyloxymethylphenyl)benzoate

(26) ethyl 3-(4'-methanesulfonyloxymethylphenyl)benzoate

(27) ethyl 4-(4'-methanesulfonyloxymethylphenyl)benzoate

(28) methyl 2-(4'-ethanesulfonyloxymethylphenyl)benzoate

(29) methyl 3-(4'-ethanesulfonyloxymethylphenyl)benzoate

(30) methyl 4-(4'-ethanesulfonyloxymethylphenyl)benzoate

(31) ethyl 2-(4'-ethanesulfonyloxymethylphenyl)benzoate

(32) ethyl 3-(4'-ethanesulfonyloxymethylphenyl)benzoate

(33) ethyl 4-(4'-ethanesulfonyloxymethylphenyl)benzoate

(34) methyl 2-(4'-p-toluenesulfonyloxymethylphenyl)benzoate

(35) methyl 3-(4'-p-toluenesulfonyloxymethylphenyl)benzoate

(36) methyl 4-(4'-p-toluenesulfonyloxymethylphenyl)benzoate

(37) ethyl 2-(4'-p-toluenesulfonyloxymethylphenyl)benzoate

(38) ethyl 3-(4'-p-toluenesulfonyloxymethylphenyl)benzoate

(39) ethyl 4-(4'-p-toluenesulfonyloxymethylphenyl)benzoate

(40) methyl 2-(4'-benzenesulfonyloxymethylphenyl)benzoate

(41) methyl 3-(4'-benzenesulfonyloxymethylphenyl)benzoate

(42) methyl 4-(4'-benzenesulfonyloxymethylphenyl)benzoate

(43) ethyl 2-(4'-benzenesulfonyloxymethylphenyl)benzoate

(44) ethyl 3-(4'-benzenesulfonyloxymethylphenyl)benzoate

(45) ethyl 4-(4'-benzenesulfonyloxymethylphenyl)benzoate

(46) 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline

(47) 4,4-dimethyl-2-(4'-bromomethyl-biphenyl-2-yl)oxazoline

(48) 4,4-dimethyl-2-(4'-chloromethyl-biphenyl-2-yl)oxazoline

(49) 4,4-dimethyl-2-(4'-methanesulfonyloxymethyl-biphenyl-2-yl)oxazoline

(50) 4,4-dimethyl-2-(4'-ethanesulfonyloxymethyl-biphenyl-2-yl)oxazoline

(51) 4,4-dimethyl-2-(4'-benzenesulfonyloxymethyl-biphenyl-2-yl)oxazoline

(52)4,4-dimethyl-2-[4'-(p-toluenesulfonyloxymethyl)biphenyl-2-yl)oxazoline

Then, the 2-amino-3-nitropyridine derivative (V) according to thepresent invention is a known substance and is represented by thefollowing general formula: ##STR11##

In the formula, R¹ and R² are each as defined above. Further, specificexamples of the 2-amino-3-nitropyridine derivative (V) according to thepresent invention include the following compounds, though the derivative(V) is not limited to them.

(1) 2-amino-4-methyl-3-nitropyridine

(2) 2-amino-4,6-dimethyl-3-nitropyridine

(3) 2-amino-5-bromo-4-methyl-3-nitropyridine

(4) 2-amino-5-chloro-4-methyl-3-nitropyridine

(5) 2-amino-5-bromo-4,6-dimethyl-3-nitropyridine

(6) 2-amino-5-chloro-4,6-dimethyl-3-nitropyridine

The 2-[N-(biphenyl-4-yl)methyl]amino-3-alkylamidopyridine derivative(VI) prepared in step 8 is represented by the following general formula:##STR12##

In the formula, R¹, R², R³ and R⁴ are each as defined above. Specificexamples of the 2-[N-(biphenyl-4-yl)methyl]amino-3-alkylamidopyridinederivative (VI) according to the present invention include the followingcompounds, though the derivative (VI) is not limited to them.

(1)3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-4-methylpyridine

(2)3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-4,6-dimethylpyridine

(3)3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4methylpyridine

(4)3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-chloro-4methylpyridine

(5)3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4,6dimethylpyridine

(6)3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-chloro-4,6dimethylpyridine

(7)3-butyrylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-4-methylpyridine

(8)3-butyrylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-4,6-dimethylpyridine

(9)3-butyrylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4-methylpyridine

(10)3-butyrylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4,6-dimethylpyridine

(11)3-valerylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-4-methylpyridine

(12)3-valerylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-4,6-dimethylpyridine

(13)3-valerylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4-methylpyridine

(14)3-valerylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4,6-dimethylpyridine

(15)3-cyclopropanecarboxamido-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-4-methylpyridine

(16)3-cyclopropanecarboxamido-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-4,6dimethylpyridine

(17)3-cyclopropanecarboxamido-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4-methylpyridine

(18)3-cyclopropanecarboxamido-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-chloro-4-methylpyridine

(19)3-cyclopropanecarboxamido-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4,6-dimethylpyridine

(20)3-cyclopropanecarboxamido-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-chloro-4,6-dimethylpyridine

(21)3-butyrylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-4-methylpyridine

(22)3-butyrylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-4,6-dimethylpyridine

(23)3-butyrylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4-methylpyridine

(24)3-butyrylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4,6-dimethylpyridine

(25)3-valerylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-4-methylpyridine

(26)3-valerylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-4,6-dimethylpyridine

(27)3-valerylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4-methylpyridine

(28)3-valerylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4,6dimethylpyridine

Then, the2-alkyl-3-(biphenyl-4-yl)methyl-6-halogeno-3H-imidazo[4,5-b]pyridinederivative (VII) is represented by the following general formula:##STR13##

In the formula, X represents a halogen atom; and R², R³ and R⁴ are eachas defined above. Further, the halogen atom is a bromine atom or achlorine atom. Furthermore, specific examples of the2-alkyl-3-(biphenyl-4-yl)methyl-6-halogeno-3H- imidazo[4,5-b]pyridinederivative (VII) according to the present invention include thefollowing compounds, though the derivative (VII) is not limited to them.

(1)2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine

(2)2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-chloro-7-methyl-3H-imidazo[4,5-b]pyridine

(3)2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(4)2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-chloro-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(5)2-n-propyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine

(6)2-n-propyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-chloro-7-methyl-3H-imidazo[4,5-b]pyridine

(7)2-n-propyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(8)2-n-propyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-chloro-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(9)2-n-butyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine

(10)2-n-butyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-chloro-7-methyl-3H-imidazo[4,5-b]pyridine

(11)2-n-butyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(12)2-n-butyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-chloro-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(13)2-ethyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine

(14)2-ethyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-chloro-7-methyl-3H-imidazo[4,5-b]pyridine

(15)2-ethyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(16)2-ethyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-chloro-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(17)2-cyclopropyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine

(18)2-cyclopropyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-chloro-7-methyl-3H-imidazo[4,5-b]pyridine

(19)2-cyclopropyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-bromo-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(20)2-cyclopropyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-chloro-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(21)2-n-propyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine

(22)2-n-propyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-chloro-7-methyl-3H-imidazo[4,5-b]pyridine

(23)2-n-propyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-bromo-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(24)2-n-propyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-chloro-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(25)2-n-butyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine

(26)2-n-butyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-chloro-7-methyl-3H-imidazo[4,5-b]pyridine

(27)2-n-butyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-bromo-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(28)2-n-butyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-chloro-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(29)2-ethyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine

(30)2-ethyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-chloro-7-methyl-3H-imidazo[4,5-b]pyridine

(31)2-ethyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-bromo-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(32)2-ethyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-6-chloro-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Then, the 2-[N-(biphenyl-4-yl)methyl]alkylamido-3-nitropyridinederivative (VIII) is represented by the following general formula:##STR14##

In the formula, R², R³ and R⁴ are each as defined above. Further,specific examples of the2-[N-(biphenyl-4-yl)methyl]alkylamido-3-nitropyridine derivative (VIII)according to the present invention include the following compounds,though the derivative (VIII) is not limited to them.

(1)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]-cyclopropanecarboxamido-4-methyl-3-nitropyridine

(2)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]-cyclopropanecarboxamido-4,6-dimethyl-3-nitropyridine

(3)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]-butyrylamino-4-methyl-3-nitropyridine

(4)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]-butyrylamino-4,6-dimethyl-3-nitropyridine

(5)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]-valerylamino-4-methyl-3-nitropyridine

(6)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]-valerylamino-4,6-dimethyl-3-nitropyridine

(7)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-4-methyl-3-nitropyridine

(8)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-4,6-dimethyl-3-nitropyridine

(9)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]butyrylamino-4-methyl-3-nitropyridine

(10)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]butyrylamino-4,6-dimethyl-3-nitropyridine

(11)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]valerylamino-4-methyl-3-nitropyridine

(12)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]valerylamino-4,6-dimethyl-3-nitropyridine

Then, the 2-alkylamido-3-nitropyridine derivative (IX) is represented bythe following general formula: ##STR15##

In the formula, R² and R³ are each as defined above. Further, specificexamples of the 2-alkylamido-3-nitropyridine derivative (IX) accordingto the present invention include the following compounds, though thederivative (IX) is not limited to them.

(1) 2-cyclopropanecarboxamido-4-methyl-3-nitropyridine

(2) 2-cyclopropanecarboxamido-4,6-dimethyl-3-nitropyridine

(3) 2-butyrylamino-4-methyl-3-nitropyridine

(4) 2-butyrylamino-4,6-dimethyl-3-nitropyridine

(5) 2-valerylamino-4-methyl-3-nitropyridine

(6) 2-valerylamino-4,6-dimethyl-3-nitropyridine

Then, the steps constituting the process of the present invention willnow be described in detail (see the above reaction scheme 4).

Step 1

This step is one wherein a 2-alkylamido-3-nitropyridine derivative (III)is obtained by reacting a 2-amino-3-nitropyridine derivative (V) with acompound represented by the general formulas R³ COZ or (R³ CO)₂ O toconduct acid amidation. In this step, the amidation is conducted byusing an acid chloride (Z=a halogen atom in the above general formula R³COZ), a carboxylic acid (Z=OH in the same formula), a mixed acidanhydride (Z=an alkoxycarbonyl group, an aryloxy-carbonyl group or anaralkyloxycarbonyl group), an acid anhydride (the above general formula(R³ CO)₂ O) or an active ester of a carboxylic acid withN-hydroxybenzotriazole or N-hydroxysuccinimide in the conventionalmanner.

Step 2

This step is one wherein the 2-alkylamido-3-nitropyridine derivative(III) is subjected to N-alkylation with an active biphenyl derivative(IV) to prepare a 2-[N-(biphenyl-4-yl)methyl]alkylamido-3-nitropyridinederivative (I).

Step 3

In this step, the 2-[N-(biphenyl-4-yl)methyl]alkylamido-3-nitropyridinederivative (I) is cyclized into a2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative(II) under reducing conditions. As the catalyst and reducing agent to beused in this step, the following combination (a catalyst and a reducingagent), for example, can be cited specifically.

a) palladium-carbon (hereinafter referred to as "Pd--C"), amine andorganic acid

b) Pd--C and hydrogen gas

c) sodium borohydride and cupric chloride

d) Pd--C and sodium hypophosphite (NaH₂ PO₂)

e) Pd--C, iron and acetic acid

The Pd--C catalyst according to the present invention may be any one sofar as it is generally used in catalytic reduction. The palladiumcontent of the catalyst is generally 2 to 20%, preferably 5 to 10%.Further, the form of the catalyst is not limited, but may be a drypowder, a wet body or an aqueous slurry. The amount of the catalyst tobe used is generally 0.001 to 10% by weight, preferably 0.01 to 5% byweight, still preferably 0.1 to 1% by weight based on the compound (I),though the amount is not limited.

The organic acid according to the present invention is a lowercarboxylic acid having 1 to 6 carbon atoms and specific examples thereofinclude formic acid, acetic acid and propionic acid.

The amine according to the present invention may be any one, so far asit can form a salt together with an organic acid such as formic acid oracetic acid. Specific examples of the amine to be generally used includetriethylamine, trimethylamine, tripropylamine, diethylamine,dimethylamine, dipropylamine, diisopropylamine, dibutylamine,N,N-dimethylethylamine, N,N-dimethylpropylamine,N,N-dimethylisopropylamine, N,N-dimethylbutylamine,N,N-dimethylhexylamine, N,N-dimethylcyclohexylamine,N,N-dimethyloctylamine, N,N-dimethyldodecylamine,N,N-dimethylbenzylamine, N,N-dimethyl-2-chloroethylamine,N,N-dimethyl-2-chloropropylamine, 2-chlorotriethylamine,N,N-diethylmethylamine, N,N,N',N'-tetramethylmethanediamine,N,N,N',N'-tetramethylethylenediamine, N,N-dimethylaniline,N,N-dimethyltoluidine, N,N-diethylaniline, ethanolamine, diethanolamine,triethanolamine, N-methylethanolamine, N,N-dimethylethanolamine,pyridine, N-methylpiperidine, N-methylmorpholine,1,4-dimethylpiperazine, N-methylpyrrole, N-methylpyrrolidine andammonia. Among these amines, triethylamine, trimethylamine,tripropylamine, diethylamine and ethanolamine are preferable, andtriethylamine is still preferable.

When triethylamine and formic acid are used as the reducing agents, thecyclization can be generally conducted according to the processdescribed in Journal of Organic Chemistry (J. Org. Chem.), 42 (22), 3491to 3494, 1977. According to the present invention, the amine is usedgenerally in an amount of 1 to 150 equivalents, preferably 1.5 to 50equivalents, still preferably 2 to 20 equivalents based on the compound(I), while the organic acid is used generally in an amount of 1 to 50equivalents, preferably 1.5 to 20 equivalents, still preferably 2 to 10equivalents based on the compound (I).

Furthermore, according to the present invention, the reductivecyclization with a combination of a Pd--C catalyst with an amine and anorganic acid may be conducted in the absence or presence of a solvent.Specific examples of the solvent to be used include, e.g., water,methanol, ethanol, n-propanol, i-propanol, butanol, tetrahydrofuran,1,2-dimethoxyethane, diethyl ether, diisopropyl ether, methyl acetate,ethyl acetate, propyl acetate, methyl propionate, ethyl propionate,1,4-dioxane, benzene, toluene, xylene, formic acid, acetic acid,propionic acid, diethylamine, triethylamine, tripropylamine,ethanolamine, n-hexane, n-octane and petroleum ether, among which water,methanol, ethanol, n-propanol, i-propanol, tetrahydrofuran,1,2-dimethoxyethane, methyl acetate, ethyl acetate, propyl acetate,methyl propionate, ethyl propionate, formic acid, acetic acid,triethylamine and toluene are preferable, and water, methanol, ethanol,ethyl acetate, tetrahydrofuran, 1,2-dimethoxyethane, triethylamine andtoluene are still preferable.

When the solvent is used, the amount thereof is generally 0.5 to 100parts by volume, preferably 0.5 to 50 parts by volume, still preferably1 to 20 parts by volume based on 1 part by weight of the compound (I),though the amount is not limited. The solvents may be used each alone oras a mixture of two or more of them.

The order of addition of the amine and the organic acid as the reducingagents is not limited. The amine may be added prior to the addition ofthe acid or the organic acid may be added prior to the addition of theamine. That is, the organic acid may be added to a suspension comprisingthe compound the catalyst, the amine and, if necessary, a solvent, orthe amine may be added to a suspension comprising the compound (I), thecatalyst, the organic acid and, if necessary, a solvent.

The reaction temperature is not particularly limited. The reaction isgenerally conducted at from 0° C. to the refluxing temperature of theamine or solvent. Although the reaction time may be from about oneminute to 48 hours, the reaction is generally completed in 30 minutes to12 hours.

When hydrogen gas is used as the reducing agent, the cyclization can becarried out under the conditions employed conventionally in organicsynthesis for catalytic reduction i.e., under the conditions of normalpressure (atmospheric pressure) to 150 kg/cm². This reaction ispreferably conducted in a solvent and the kind and amount of the solventand the temperature and time of the reaction may be the same as thosedescribed above for the case of using an amine and an organic acid asthe reducing agents.

When sodium borohydride and cupric chloride are used as the reducingagents, the amount of sodium borohydride to be used is generally about 1to 100 equivalents, preferably 2 to 80 equivalents, still preferably 5to 50 equivalents based on the compound (I), though the amount is notlimited. On the other hand, the amount of cupric chloride to be used isgenerally 1 to 50 equivalents, preferably 2 to 30 equivalents, stillpreferably 5 to 20 equivalents based on the compound (I). This reactionis also preferably conducted in a solvent and the kind and amount of thesolvent and the temperature and time of the reaction may be the same asthose described above for the case of using an amine and an organic acidas the reducing agents.

When sodium hypophosphite is used as the reducing agent, the amountthereof is generally 1 to 100 equivalents, preferably 2 to 50equivalents, still preferably 5 to 20 equivalents based on the compound(I), though the amount is not limited. This reaction is also preferablyconducted in a solvent and the kind and amount of the solvent and thetemperature and time of the reaction may be the same as those describedabove for the case of using an amine and an organic acid as the reducingagents.

When iron and acetic acid are used as the reducing agents, the amountsof them are not limited. The amount of iron used is generally 1 to 100equivalents, preferably 5 to 75 equivalents, still preferably 10 to 50equivalents based on the compound (I), while the amount of acetic acidused is generally 1 to 500 equivalents, preferably 10 to 300equivalents, still preferably 50 to 200 equivalents based on thecompound (I). When a solvent is used in this reaction, the kind andamount of the solvent to be used and the temperature and time of thereaction may be the same as those described above for the case of usingan amine and an organic acid as the reducing agents, though thisreaction may be carried out in the absence of any solvent.

Steps 4 and 5

In step 4, only the 5-position halogen atom of the pyridine ring in the2-[N-(biphenyl-4-yl)methyl]alkylamido-3-nitro-pyridine derivative (I) isselectively reduced, i.e., replaced by a hydrogen atom, while in step 5,only the 5-position halogen atom of the pyridine ring in the2-alkylamido-5-halogeno-3-nitropyridine derivative (III) is selectivelyreduced, i.e., replaced by a hydrogen atom. These steps can be conductedby using the Pd--C catalyst and amine and organic acid as thosedescribed in explanation of step 3 as a combination of a catalyst and areducing agent and by employing the same conditions as those of step 3with respect to the solvent and reaction temperature. The reaction timeis generally 5 minutes to 7 hours, preferably 30 minutes to 6 hours,still preferably 1 to 5 hours. Step 4 gives a2-[N-(biphenyl-4-yl)methyl]alkylamido-3-nitropyridine derivative (VIII),while the step 5 gives a 2-alkylamido-3-nitropyridine derivative (IX).

Step 6

This step is one wherein a2-[N-(biphenyl-4-yl)methyl]alkylamido-3-nitropyridine derivative (VIII)is prepared from the 2-alkylamido-3-nitropyridine derivative (IX) whichhas been prepared in the step 5 by replacing the halogen atom present atthe 5-position of the pyridine ring with a hydrogen atom throughN-alkylation, and can be conducted in the same manner as that of thestep 2.

Step 7

This step is one wherein a2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative(II) is prepared from the2-[N-(biphenyl-4-yl)methyl]alkylamido-3-nitropyridine derivative (VIII)which has been prepared in steps 4 or 6 and has a hydrogen atom at the5-position through cyclization under reductive conditions.

In this step, the reductive cyclization can be conducted with the samecombination of a catalyst and a reducing agent as that described abovein explanation of step 3 under the same conditions as those describedabove in explanation of step 3. Alternatively, the reductive cyclizationmay be conducted by using any of the following reducing agents in theconventional manner:

a) iron and acetic acid

b) iron and hydrochloric acid

Step 8

This step is one wherein the2-[N-(biphenyl-4-yl)methyl]alkylamido-3-nitropyridine derivative (I) isreductive isomerized with activated carbon, hydrazine and ferricchloride to form a 2-[N-(biphenyl-4-yl)methyl]amino-3-alkylamidopyridinederivative (VI). Although the amounts of activated carbon, hydrazine andferric chloride used are not limited, activated carbon is generally usedin an amount of 1 to 50% by weight, preferably 3 to 40% by weight, stillpreferably 5 to 30% by weight based on the compound (I); hydrazinegenerally in an amount of 1 to 50 equivalents, preferably 1.5 to 20equivalents, still preferably 2 to 10 equivalents based on the compound(I); and ferric chloride generally in an amount of 1 to 50 equivalents,preferably 1.5 to 20 equivalents, still preferably 2 to 10 equivalentsbased on the compound (I). This step is preferably conducted in thepresence of a solvent. The kind of the solvent and the reactiontemperature may be the same as those of the case of using an amine andan organic acid in step 3. The reaction time is generally completedwithin 48 hours.

Step 9

This step is one wherein a2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative isprepared from the 2-[N-(biphenyl-4-yl)methyl]amino-3alkylamidopyridinederivative (VI) which has been prepared in step 8 through cyclizationunder acidic conditions. This reaction is not limited so far as it isconducted in the presence of any acid which is used in a conventionalorganic synthesis. The reaction is conducted with, for example,specifically, an inorganic acid such as hydrochloric acid, sulfuricacid, nitric acid, hydrobromic acid, hydroiodic acid, perchloric acid,phosphoric acid and polyphosphoric acid; or a sulfonic acid such asmethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andcamphorsulfonic acid, under acidic conditions.

This step is also preferably conducted in the presence of a solvent.Specific examples of the solvent include tetrahydrofuran,1,2-dimethoxyethane, diethyl ether, diisopropyl ether, methyl acetate,ethyl acetate, propyl acetate, methyl propionate, ethyl propionate,1,4-dioxane, benzene, toluene, xylene, formic acid, acetic acid,propionic acid, n-hexane, n-octane and petroleum ether, among whichtetrahydrofuran, 1,2-dimethoxyethane, formic acid, acetic acid,propionic acid, benzene, toluene and xylene are preferable, and formicacid, acetic acid, benzene, toluene and xylene are still preferable. Thesolvent is generally used in an amount of 0.5 to 100 parts by volume,preferably 0.5 to 50 parts by volume, still preferably 1 to 20 parts byvolume based on 1 part by weight of the compound (VI), though the amountthereof is not limited. The above solvents may be used each alone or asa mixture of two or more of them.

Further, though the reaction temperature is not particularly limited,the reaction is generally conducted at from 0° C. to the refluxingtemperature of the amine or solvent. Furthermore, in this step, thereaction can be accelerated by removing formed water from the reactionsystem by adding a dehydrating agent such as a molecular sieve or byforming an azeotropic mixture. In such a case, the reaction time isgenerally completed within 12 hours.

Step 10

This step is one wherein the2-[N-(biphenyl-4-yl)methyl]alkylamido-3-nitropyridine derivative (I)having a substituent halogen atom at the 5-position is reductivelycyclized without the elimination of the halogen atom. The reductivecyclization in this step may be conducted by the use of iron and aceticacid or iron and hydrochloric acid in the conventional manner.

Step 11

This step is one wherein the2-alkyl-3-(biphenyl-4-yl)methyl-6-halogeno-3H-imidazo[4,5-b]-pyridinederivative (VII), which is one of compounds prepared in step 10 and hasa substituent halogen atom at the B-position, is reductivelydehalogenated into an objective2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative(II). This step may be conducted in the same manner as that of step 3.

This step is one wherein the2-[N-(biphenyl-4-yl)methyl]amino-3-alkylamidopyridine derivative (VI)prepared in step 8 is reduced and dehalogenated into an objective2,alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative(II). This step may be conducted in the same manner as that of step 3.

Step 13

The imidazopyridine derivatives which is disclosed in Japanese PatentPublication-A Nos. 3-95181 and 3-236377 and is useful as antagonistsagainst angiotensin II receptor, include2-cyclopropyl-3-(2'-carboxylbiphenyl-4-yl)-methyl-7-methyl-3H-imidazo[4,5-b]pyridineor the like and are compounds having a carboxyl group. To obtain thesecompounds, the ester group or the oxazoline group of2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivatives(II) (such as2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo-[4,5-b]pyridine)prepared according to the process of the present invention is subjectedto a conventional hydrolysis in the production of them. Among theseimidazoline derivatives having a carboxyl group, one having acyclopropyl group at the 2-position is particularly excellent in theantagonism against angiotensin II receptor and therefore is highlyuseful as an antihypertensive drug or a remedy for hemal lesions.According to the process for the preparation of a2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative(II) of the present invention, a precursor of such an antagonist againstangiotensin II receptor can be prepared. Then, the2-alkylamido-3-nitropyridine derivative (X) represented by the followinggeneral formula is a novel compound and is useful as an intermediate forthe preparation of the2-alkyl-3-(biphenyl-4-yl)-methyl-3H-imidazo[4,5-b]pyridine derivative(II): ##STR16##

In the formula, R¹ R² and R³ are each as defined above. R⁶ represents ahydrogen atom or a group represented by the following general formula:##STR17## (wherein R⁷ represents a group represented by the followinggeneral formula:

    --COOR.sup.8

{wherein R⁸ represents a lower alkyl group, a cycloalkyl group, analkoxyalkyl group, a thioalkoxyalkyl group, a cycloether group, an arylgroup, an aralkyl group, an alkenyl group, an alkenyl group or atrialkylsilyl group} or a group represented by the following generalformula: ##STR18## Specific examples of R⁸ include the same groups asthose described with respect to R⁵ in the above2-[N-(2'-biphenyl-4-yl)methyl]alkylamido-3-nitropyridine derivative (I).Further, specific examples of the 2-alkylamido-3-nitropyridinederivative (X) according to the present invention include the followingcompounds, though the derivative (X) is not limited to them.

(1)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-4-methyl-3-nitropyridine

(2)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-4,6-dimethyl-3-nitropyridine

(3)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine

(4)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-chloro-4-methyl-3nitropyridine

(5)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4,6-dimethyl-3nitropyridine

(6)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-chloro-4,6-dimethyl-3nitropyridine

(7)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]butyrylamino-4-methyl-3-nitropyridine

(8)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]butyrylamino-4,6-dimethyl-3-nitropyridine

(9)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]butyrylamino-5-bromo-4-methyl-3-nitropyridine

(10)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]butyrylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(11)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]valerylamino-4-methyl-3-nitropyridine

(12)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]valerylamino-4,6-dimethyl-3-nitropyridine

(13)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]valerylamino-5-bromo-4-methyl-3-nitropyridine

(14)2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]valerylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(15)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-4-methyl-3-nitropyridine

(16)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-4,6-dimethyl-3-nitropyridine

(17)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine

(18)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-5-chloro-4-methyl-3-nitropyridine

(19)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-5-bromo-4,6-dimethyl-3-nitropyridine

(20)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]cyclopropanecarboxamido-5-chloro-4,6-dimethyl-3-nitropyridine

(21)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]butyrylamino-4-methyl-3-nitropyridine

(22)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]butyrylamino-4,6-dimethyl-3-nitropyridine

(23)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]butyrylamino-5-bromo-4-methyl-3-nitropyridine

(24)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]butyrylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(25)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]valerylamino-4-methyl-3-nitropyridine

(26)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]valerylamino-4,6-dimethyl-3-nitropyridine

(27)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]valerylamino-5-bromo-4-methyl-3-nitropyridine

(28)2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]valerylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(29) 2-cyclopropanecarboxamido-4-methyl-3-nitropyridine

(30) 2-cyclopropanecarboxamido-4,6-dimethyl-3-nitropyridine

(31) 2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine

(32) 2-cyclopropanecarboxamido-5-chloro-4-methyl-3-nitropyridine

(33) 2-cyclopropanecarboxamido-5-bromo-4,6-dimethyl-3-nitropyridine

(34) 2-cyclopropanecarboxamido-5-chloro-4,6-dimethyl-3-nitropyridine

(35) 2-butyrylamino-4-methyl-3-nitropyridine

(36) 2-butyrylamino-4,6-dimethyl-3-nitropyridine

(37) 2-butyrylamino-5-bromo-4-methyl-3-nitropyridine

(38) 2-butyrylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(39) 2-valerylamino-4-methyl-3-nitropyridine

(40) 2-valerylamino-4,6-dimethyl-3-nitropyridine

(41) 2-valerylamino-5-bromo-4-methyl-3-nitropyridine

(42) 2-valerylamino-5-bromo-4,6-dimethyl-3-nitropyridine

The 2-[N-(biphenyl-4-yl)methyl]amino-3-alkylamidopyridine derivative(VI) represented by the following general formula is also a novelcompound and is useful as an intermediate for the preparation of the2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridine derivative(II): ##STR19##

In the formula, R¹, R², R³ and R⁴ are each as defined above. Further,specific examples of the2-[N-(biphenyl-4-yl)methyl]amino-3-alkylamidopyridine derivative (VI)according to the present invention include the following compounds,though the derivative (VI) is not limited to them.

(1)3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-4-methylpyridine

(2)3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-4,6-dimethylpyridine

(3)3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4methylpyridine

(4)3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-chloro-4methylpyridine

(5)3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4,6dimethylpyridine

(6)3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-chloro-4,6dimethylpyridine

(7)3-butyrylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-4-methylpyridine

(8)3-butyrylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-4,6-dimethylpyridine

(9)3-butyrylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4-methylpyridine

(10)3-butyrylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4,6-dimethylpyridine

(11)3-valerylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-4-methylpyridine

(12)3-valerylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-4,6-dimethylpyridine

(13)3-valerylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4-methylpyridine

(14)3-valerylamino-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4,6-dimethylpyridine

(15)3-cyclopropanecarboxamido-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-4-methyl-pyridine

(16)3-cyclopropanecarboxamido-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-4,6dimethylpyridine

(17)3-cyclopropanecarboxamido-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4-methylpyridine

(18)3-cyclopropanecarboxamido-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-chloro-4-methylpyridine

(19)3-cyclopropanecarboxamido-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4,6-dimethylpyridine

(20)3-cyclopropanecarboxamido-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-chloro-4,6-dimethylpyridine

(21)3-butyrylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-4-methylpyridine

(22)3-butyrylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-4,6-dimethylpyridine

(23)3-butyrylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4-methylpyridine

(24)3-butyrylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4,6-dimethylpyridine

(25)3-valerylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-4-methylpyridine

(26)3-valerylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-4,6-dimethylpyridine

(27)3-valerylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4-methylpyridine

(28)3-valerylamino-2-[N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4,6-dimethylpyridine

Compounds in which R⁴ represents --COOR⁵ and is present at 2'-positionof the biphenyl in the above description, and the application of theprocess according to the present invention in the production of thecompounds are particularly preferably.

Then, the present inventors have extensively studied for solving theproblems of the process of the prior art. As a result, they have foundthat the above object can be attained by employing any of the followingprocesses to enable an industrially preparation of a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II), and have accomplished the present invention.

(1) subjecting a2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkylamido-5-halogeno-3-nitropyridinederivative (I) to cyclization and dehalogenation under reducingconditions.

(2) reacting a 2-alkylamido-5-halogeno-3-nitropyridine derivative (III)with an active biphenyl derivative (IV) to form a2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkylamido-5-halogeno-3-nitropyridinederivative (I) through N-alkylation and then subjecting it tocyclization and dehalogenation under reducing conditions.

(3) reacting a 2-amino-5-halogeno-3-nitropyridine derivative (V) with acompound represented by the general formula: R² COZ or (R² CO)₂ O toform a 2-alkylamido-5-halogeno-3-nitropyridine derivative (III),reacting it with an active biphenyl derivative (IV) to form a2-[N-(2'-cyanobiphenyl-4-yl)methyl]-alkylamido-5-halogeno-3-nitropyridinederivative (I) through N-alkylation, and then subjecting it tocyclization and dehalogenation under reducing conditions.

(4) subjecting a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-halogeno-3H-imidazo[4,5-b]pyridinederivative (VI) to reductive dehalogenation.

(5) subjecting a2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkylamido-5-halogeno-3-nitropyridinederivative (I) to reductive cyclization with iron and acetic acid oriron and hydrochloric acid to form a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-halogeno-3H-imidazo[4,5-b]pyridinederivative (VI) and then subjecting it to reductive dehalogenation. (

6) cyclizing a2-[N-(2'-cyanobiphenyl-4-yl)methyl]-amino-5-halogeno-3-alkylamidopyridinederivative (VII) under acidic conditions into a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-halogeno-3H-imidazo[4,5-b]pyridinederivative (VI), and then subjecting it to reductive dehalogenation.

(7) subjecting to a2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkylamido-5-halogeno-3-nitropyridinederivative (I) to reductive isomerization with activated carbon,hydrazine and ferric chloride to form a2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-halogeno-3-alkylamidopyridinederivative (VII), then cyclizing it under acidic conditions into a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-halogeno-3H-imidazo[4,5-b]pyridinederivative (VI), and further conducting reduction.

(8) subjecting a2-[N-(2'-cyanobiphenyl-4-yl)methyl]-alkylamido-5-halogeno-3-nitropyridinederivative (I) to selective reductive dehalogenation to form a2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkylamido-3-nitropyridine derivative(VIII) and then cyclizing it under reducing conditions.

(9) subjecting a2-[N-(2'-cyanobiphenyl-4-yl)methyl]-amino-5-halogeno-3-alkylamidopyridinederivative (VII) to cyclization and dehalogenation under reducingconditions.

(10) subjecting a2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkylamido-5-halogeno-3-nitropyridinederivative (I) to reductive isomerization with activated carbon,hydrazine and ferric chloride to form a2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-halogeno-3-alkylamidopyridinederivative (VII) and then subjecting it to cyclization anddehalogenation under reducing conditions.

Furthermore, according to the present invention, the 5-position halogenatom can be eliminated and replaced by a hydrogen atom simultaneouslywith the reductive cyclization of the final step, so that the process ofthe present invention can dispense with the additional, industriallydisadvantageous dehalogenation step with n-butyllithium unlike theprocess of the Japanese Patent Publication-A No. 3-95181, thus beingextremely excellent. Alternatively, the dehalogenation may beselectively conducted prior to the reductive cyclization of the compound(I). The outline of the reaction path according to the present inventionis represented by the following chemical reaction formula (reactionscheme-5): ##STR20##

Accordingly, an object of the present invention is to provide anindustrially advantageous process for preparing a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II) which is a precursor of an antagonist againstangiotensin II receptor useful as an antihypertensive drug or a remedyfor hemal lesions.

The 2-amino-5-halogeno-3-nitropyridine derivative (V) to be used as thestarting material in step 1 (see the above reaction Scheme-5, the sameapplies hereinafter) according to the present invention is representedby the following chemical structural formula: ##STR21##

In the formula, X represents a halogen atom; and R¹ represents ahydrogen atom or a methyl group, with the proviso that the halogen atomis a bromine atom or a chlorine atom. Specific examples of thederivative (V) include the following compounds.

(1) 2-amino-5-bromo-4-methyl-3-nitropyridine

(2) 2-amino-5-chloro-4-methyl-3-nitropyridine

(3) 2-amino-5-bromo-4,6-dimethyl-3-nitropyridine

(4) 2-amino-5-chloro-4,6-dimethyl-3-nitropyridine

The derivative (V) can be prepared by converting a 2-aminopyridinederivative into a 2-amino-5-bromopyridine derivative or a2-amino-5-chloropyridine derivative through bromination or chlorinationaccording to the process described in Journal of American ChemicalSociety (J.A.C.S.), 79, 6421 to 6426, 1957 or Journal of OrganicChemistry (J. Org. Chem.), 24, 1455 to 1460, 1959 and nitrating theobtained 5-halogenopyridine derivative in the conventional manner.

The 2-alkylamido-5-halogeno-3-nitropyridine derivative (III) obtained byconducting step 1 is represented by the following chemical structuralformula: ##STR22##

In the formula, R¹ and X are each as defined above and R² represents acycloalkyl group, a lower alkyl group or a lower alkoxy group. Specificexamples of cycloalkyl groups in the definition of R² include acyclopropyl group, a cyclobutyl group, a cyclopentyl group and acyclohexyl group; those of lower alkyl groups include alkyl groupshaving 1 to 6 carbon atoms, e.g., a methyl group, an ethyl group, an-propyl group, an i-propyl group, a n-butyl group, an i-butyl group, at-butyl group, an amyl group and a hexyl group; and those of loweralkoxy groups include lower alkoxy groups having 1 to 6 carbon atoms,e.g., a methoxy group, an ethoxy group, a n-propoxy group, an i-propoxygroup, a butoxy group, a pentyloxy group and a hexyloxy group. Further,specific examples of the 2-alkylamido-5-halogeno-3-nitropyridinederivative (III) according to the present invention include thefollowing compounds, though the derivative (III) is not limited to them.

(1) 2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine

(2) 2-cyclopropanecarboxamido-5-bromo-4,6-dimethyl-3-nitropyridine

(3) 2-cyclopropanecarboxamido-5-chloro-4-methyl-3-nitropyridine

(4) 2-cyclopropanecarboxamido-5-chloro-4,6-dimethyl3-nitropyridine

(5) 2-n-butyrylamino-5-bromo-4-methyl-3-nitropyridine

(6) 2-n-butyrylamino-S-bromo-4,6-dimethyl-3-nitropyridine

(7) 2-n-butyrylamino-5-chloro-4-methyl-3-nitropyridine

(8) 2-n-butyrylamino-5-chloro-4,6-dimethyl-3-nitropyridine

(9) 2-n-valerylamino-5-bromo-4-methyl-3-nitropyridine

(10) 2-n-valerylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(11) 2-n-valerylamino-5-chloro-4-methyl-3-nitropyridine

(12) 2-n-valerylamino-5-chloro-4,6-dimethyl-3-nitropyridine

The2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkylamido-5-halogeno-3-nitropyridinederivative (I) obtained as the result of step 2 has the followingchemical structural formula: ##STR23##

In the formula, R¹ R² and X are each as defined above. Furthermore,specific, representative examples of the compound (I) according to thepresent invention include, e.g., the following compounds, though thecompound (I) is not limited to them.

(1)2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine

(2)2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4,6-dimethyl-3-nitropyridine

(3)2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-chloro-4-methyl-3-nitropyridine

(4)2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-chloro-4,6-dimethyl-3-nitropyridine

(5)2-[N-(2'-cyanobiphenyl-4-yl)methyl]butyrylamino-5-bromo-4-methyl-3-nitropyridine

(6)2-[N-(2'-cyanobiphenyl-4-yl)methyl]butyrylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(7)2-[N-(2'-cyanobiphenyl-4-yl)methyl]butyrylamino-5-chloro-4,6-dimethyl-3-nitropyridine

(8)2-[N-(2'-cyanobiphenyl-4-yl)methyl]butyrylamino-5-chloro-4-methyl-3-nitropyridine

(9)2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-5-bromo-4-methyl-3-nitropyridine

(10)2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(11)2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-5-chloro-4-methyl-3-nitropyridine

(12)2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-5-chloro-4,6-dimethyl-3-nitropyridine

Then, the 2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkylamido-3-nitropyridinederivative (VIII) obtained as the result of step 4 has the followingchemical structural formula: ##STR24##

In the formula, R¹ and R² are each as defined above. Further specificand representative examples of the compound (VIII) according to thepresent invention include the following compounds, though the compound(VIII) is not limited to them.

(1)2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-4-methyl-3-nitropyridine

(2)2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-4,6-dimethyl-3-nitropyridine

(3)2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-4-methyl-3-nitropyridine

(4)2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-4,6-dimethyl-3-nitropyridine

(5)2-[N-(2'-cyanobiphenyl-4-yl)methyl]butyrylamino-4-methyl-3-nitropyridine

(6)2-[N-(2'-cyanobiphenyl-4-yl)methyl]butyrylamino-4,6-dimethyl-3-nitropyridine

(7)2-[N-(2'-cyanobiphenyl-4-yl)methyl]butyrylamino-4-methyl-3-nitropyridine

(8)2-[N-(2'-cyanobiphenyl-4-yl)methyl]butyrylamino-4,6-dimethyl-3-nitropyridine

(9)2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-4-methyl-3-nitropyridine

(10)2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-4,6-dimethyl-3-nitropyridine

(11)2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-4-methyl-3-nitropyridine

(12)2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-4,6-dimethyl-3-nitropyridine

Then, the2-[N-(2'-cyanobiphenyl-4-yl)methyl]-amino-5-halogeno-3-alkylamidopyridinederivative (VII) obtained as the result of step 6 has the followingchemical structural formula: ##STR25##

In the formula, R¹ R² and X are each as defined above. Further specificand representative examples of the compound (VII) according to thepresent invention include the following compounds, though the compound(VII) is not limited to them

(1)3-cyclopropanecarboxamido-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-bromo-4-methylpyridine

(2)3-cyclopropanecarboxamido-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-bromo-4,6-dimethylpyridine

(3)3-cyclopropanecarboxamido-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-chloro-4-methylpyridine

(4)3-cyclopropanecarboxamido-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-chloro-4,6-dimethylpyridine

(5)3-n-butyrylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-bromo-4-methylpyridine

(6)3-n-butyrylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-bromo-4,6-dimethylpyridine

(7)3-n-butyrylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-chloro-4-methylpyridine

(8)3-n-butyrylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-chloro-4,6-dimethylpyridine

(9)3-n-valerylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-bromo-4-methylpyridine

(10)3-n-valerylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-bromo-4,6-dimethylpyridine

(11)3-n-valerylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-chloro-4-methylpyridine

(12)3-n-valerylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-chloro-4,6-dimethylpyridine

Then, the2-alkyl-3-(2'-cyanobiphenyl-4-yl)-methyl-6-halogeno-3H-imidazo[4,5-b]pyridinederivative (VI) obtained by conducting steps 8 or 10 has the followingstructural formula: ##STR26##

In the formula, R¹, R² and X are each as defined above. Further specificand representative examples of the compound (VI) according to thepresent invention include the following compounds, though the compound(VI) is not limited to them.

(1)2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine

(2)2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(3)2-n-propyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine

(4)2-n-propyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(5)2-n-butyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine

(6)2-n-butyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(7)2-ethyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine

(8)2-ethyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Further, the2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II) obtained by conducting steps 3, 5, 7 or 9 is representedby the following chemical structural formula: ##STR27##

In the formula, R¹ and R² are each as defined above. Further, specificand representative examples of the compound (II) according to thepresent invention include the following compounds, though the compound(II) is not limited to them.

(1)2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

(2)2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(3)2-n-propyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

(4)2-n-propyl-3-(2'-cyanobiphenyl-4-yl)methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(5)2-n-butyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

(6)2-n-butyl-3-(2'-cyanobiphenyl-4-yl)methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

(7)2-ethyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

(8)2-ethyl-3-(2'-cyanobiphenyl-4-yl)methyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Next, each step of the process according to the present invention willbe described in detail hereinafter (see the above reaction scheme-5).

Step 1

This step is one wherein a 2-amino-5-halogeno-3-nitropyridine derivative(V) is reacted with a compound represented by the general formulas R²COZ or (R² CO)₂ O to conduct amidation to obtain a2-alkylamido-5-halogeno-3-nitropyridine derivative (III). In this step,the amidation is conducted by using an acid chloride (Z= a halogen atomin the above general formula R² COZ), a carboxylic acid (Z=OH in thesame formula), a mixed acid anhydride (Z= an alkoxycarbonyl group, anaryloxycarbonyl group or an aralkyloxycarbonyl group), an acid anhydride(the above general formula ((R² CO)₂ O) or an active ester of acarboxylic acid with N-hydroxybenozotriazole or N-hydroxysuccinimide inthe conventional manner.

Step 2

This step is one wherein a2-[N-(2'cyanobiphenyl-4-yl)methyl]alkylamido-5-halogeno-3-nitropyridinederivative (I) is prepared from the2-alkylamido-5-halogeno-3-nitropyridine derivative (III). In conductingthis step or step 6, an active biphenyl derivative (IV) represented bythe following general formula is used as an N-alkylating agent:##STR28## [wherein Y represents a leaving group used in the conventionalorganic synthesis, for example, a halogen atom, a methanesulfonyloxygroup, an ethanesulfonyloxy group, a benzenesulfonyloxy group or atoluenesulfonyloxy group].

Specific examples thereof to be used include2-(4'-bromomethylphenyl)benzonitrile,2-(4'-chloromethylphenyl)benzonitrile,2-(4'-methanesulfonyloxymethylphenyl)benzonitrile,2-(4'-ethanesulfonyloxymethylphenyl)benzonitrile,2-(4'-benzenesulfonyloxymethylphenyl)benzonitrile and2-(4'-toluenesulfonyloxymethylphenyl)benzonitrile, which can be obtainedby the producing process described in, e.g., the Japanese PatentPublication-A No. 3-236377 and according to the process which will bedescribed below.

Step 3

This step is one wherein the 2-[N-(2'-cyano-biphenyl-4-yl)methyl]alkylamido-5-halogeno-3-nitropyridine derivative(I) is cyclized and dehalogenated into a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II) under reducing conditions. As the catalyst and reducingagent to be used in this step, the following combinations (a catalystand a reducing agent), for example, can be cited specifically.

a) palladium-carbon (hereinafter referred to as

"Pd--C"), amine and organic acid

b) Pd--C and hydrogen gas

c) sodium borohydride and cupric chloride

d) Pd--C and sodium hypophosphite (NaH₂ PO₂)

e) Pd--C, iron and acetic acid

The Pd--C catalyst according to the present invention may be any one sofar as it is generally used in catalytic reduction. The palladiumcontent of the catalyst is generally 2 to 20%, preferably 5 to 10%.Further, the form of the catalyst is not limited, but may be a drypowder, a wet body or an aqueous slurry. The amount of the catalyst tobe used is generally 0.001 to 104 by weight, preferably 0.01 to 5% byweight, still preferably 0.1 to 1% by weight based on the compound (I),though the amount is not limited.

The organic acid according to the present invention is a lowercarboxylic acid having 1 to 6 carbon atoms and specific examples thereofinclude formic acid, acetic acid and propionic acid.

The amine according to the present invention may be any one, so far asit can form a salt together with an organic acid such as formic acid oracetic acid. Specific examples of the amine to be generally used includetriethylamine, trimethylamine, tripropylamine, diethylamine,dimethylamine, dipropylamine, diisopropylamine, dibutylamine,N,N-dimethylethylamine, N,N-dimethylpropylamine,N,N-dimethylisopropylamine, N,N-dimethylbutylamine,N,N-dimethylhexylamine, N,N-dimethylcyclohexylamine,N,N-dimethyloctylamine, N,N-dimethyldodecylamine,N,N-dimethylbenzylamine, N,N-dimethyl-2-chloroethylamine,N,N-dimethyl-2-chloropropylamine, 2-chlorotriethylamine,N,N-diethylmethylamine, N,N,N',N'-tetramethylmethanediamine,N,N,N',N'-tetramethylethylenediamine, N,N-dimethylaniline,N,N-dimethyltoluidine, N,N-diethylaniline, ethanolamine, diethanolamine,triethanolamine N-methylethanolamine, N,N-dimethylethanolamine,N-methylpiperidine, N-methylmorpholine, 1,4-pyridine,dimethylpiperazine, N-methylpyrrole, N-methylpyrrolidine and ammonia.Among these amines, triethylamine, trimethylamine, tripropylamine,diethylamine and ethanolamine are preferable, and triethylamine is stillpreferable.

When triethylamine and formic acid are used as the reducing agents, thecyclization can be generally conducted according to the processdescribed in Journal of Organic Chemistry (J. Org. Chem.), 42, (22) 8491to 8494, 1977. According to the present invention, the amine is usedgenerally in an amount of 1 to 150 equivalents, preferably 1.5 to 50equivalents, still preferably 2 to 20 equivalents based on the compound(I), while the organic acid is used generally in an amount of 1 to 50equivalents, preferably 1.5 to 20 equivalents, still preferably to 10equivalents based on the compound (I).

Furthermore, according to the present invention, the reductivecyclization with a combination of a Pd--C catalyst with an amine and anorganic acid may be conducted in the absence or presence of a solvent.Specific examples of the solvent to be used include, e.g., water,methanol, ethanol, n-propanol, i-propanol, butanol, tetrahydrofuran,1,2-dimethoxyethane, diethyl ether, diisopropyl ether, methyl acetate,ethyl acetate, propyl acetate, methyl propionate, ethyl propionate,1,4-dioxane, benzene, toluene, xylene, formic acid, acetic acid,propionic acid, diethylamine, triethylamine, tripropylamine,ethanolamine, n-hexane, n-octane and petroleum ether, among which water,methanol, ethanol, n-propanol, i-propanol, tetrahydrofuran,1,2-dimethoxyethane, methyl acetate, ethyl acetate, propyl acetate,methyl propionate, ethyl propionate, formic acid, acetic acid,triethylamine and toluene are preferable, and water, methanol, ethanol,ethyl acetate, tetrahydrofuran, 1,2-dimethoxyethane, triethylamine andtoluene are still preferable.

When the solvent is used, the amount thereof is generally 0.5 to 100parts by volume, preferably 0.5 to 50 parts by volume, still preferably1 to 20 parts by volume based on 1 part by weight of the compound (I),though the amount is not limited. The solvents may be used each alone oras a mixture of two or more of them.

The order of addition of the amine and the organic acid as the reducingagents is not limited. The amine may be added prior to the addition ofthe acid or the organic acid may be added prior to the addition of theamine. That is, the organic acid may be added to a suspension comprisingthe compound (I), the catalyst, the amine and, if necessary, a solvent,or the amine may be added to a suspension comprising the compound (I),the catalyst, the organic acid and, if necessary, a solvent.

The reaction temperature is not particularly limited. The reaction isgenerally conducted at from 0° C. to the refluxing temperature of theamine or solvent. Although the reaction time may be from about oneminute to 48 hours, the reaction is generally completed in 30 minutes to12 hours.

When hydrogen gas is used as the reducing agent, the cyclization can becarried out under the conditions employed conventionally in organicsynthesis for catalytic reduction i.e., under the conditions of normalpressure (atmospheric pressure) to 150 kg/cm². This reaction ispreferably conducted in a solvent and the kind and amount of the solventand the temperature and time of the reaction may be the same as thosedescribed above for the case of using an amine and an organic acid asthe reducing agents.

When sodium borohydride and cupric chloride are used as the reducingagents, the amount of sodium borohydride to be used is generally about 1to 100 equivalents, preferably 2 to 80 equivalents, still preferably 5to 50 equivalents based on the compound (I), though the amount is notlimited. On the other hand, the amount of cupric chloride to be used isgenerally 1 to 50 equivalents, preferably 2 to 30 equivalents, stillpreferably 5 to 20 equivalents based on the compound (I). This reactionis also preferably conducted in a solvent and the kind and amount of thesolvent and the temperature and time of the reaction may be the same asthose described above for the case of using an amine and an organic acidas the reducing agents.

When sodium hypophosphite is used as the reducing agent, the amountthereof is generally 1 to 100 equivalents, preferably 2 to 50equivalents, still preferably 5 to 20 equivalents based on the compound(I), though the amount is not limited. This reaction is also preferablyconducted in a solvent and the kind and amount of the solvent and thetemperature and time of the reaction may be the same as those describedabove for the case of using an amine and an organic acid as the reducingagents.

When iron and acetic acid are used as the reducing agents, the amountsof them are not limited. The amount of iron used is generally 1 to 100equivalents, preferably 5 to 75 equivalents, still preferably 10 to 50equivalents based on the compound (I), while the amount of acetic acidused is generally 1 to 500 equivalents, preferably 10 to 300equivalents, still preferably 50 to 200 equivalents based on thecompound (I). When a solvent is used in this reaction, the kind andamount of the solvent to be used and the temperature and time of thereaction may be the same as those described above for the case of usingan amine and an organic acid as the reducing agents, though thisreaction may be carried out in the absence of any solvent.

Step 4

Step 4 is one wherein only the 5-position halogen atom of the pyridineskeleton in the2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkylamido-5-halogeno-3-nitropyridinederivative (I) is selectively reduced, i.e., replaced by a hydrogenatom, to form a2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkylamido-3-nitropyridine derivative(VIII). This step can be conducted by using the same amine and organicacid as those described in explanation of step 3 as a combination of acatalyst and a reducing agent and by employing the same conditions asthose of step 3 with respect to the solvent and reaction temperature aswell. However, the reaction time is generally 5 minutes to 7 hours,preferably 30 minutes to 6 hours, still preferably 1 to 5 hours.

Step 5

Step 5 is one wherein the2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkylamido-3-nitropyridine derivative(VIII) obtained by conducting step 4 is cyclized into a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II) under reducing conditions.

In this step, the reductive cyclization can be conducted by using thesame combination of a catalyst and a reducing agent as that described inexplanation of step 3 under the same conditions as those described inexplanation of step 3. Alternatively, the reductive cyclization may beconducted by using any of the following reducing agents in theconventional manner.

a) iron and acetic acid

b) iron and hydrochloric acid

Step 6

This step is one wherein the2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkylamido-5-halogeno-3-nitropyridinederivative (I) is reductively isomerized with activated carbon,hydrazine and ferric chloride to form a2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-halogeno-3-alkylamidopyridinederivative (VII). Although the amounts of activated carton, hydrazineand ferric chloride used are not limited, activated carbon is generallyused in an amount of 1 to 50% by weight, preferably 3 to 40% by weight,still preferably 5 to 30% by weight based on the compound (I); hydrazineis generally in an amount of 1 to 50 equivalents, preferably 1.5 to 20equivalents, still preferably 2 to 10 equivalents based on the compound.(I); and ferric chloride is generally in an amount of 1 to 50equivalents, preferably in an amount of 1.5 to 20 equivalents, stillpreferably 2 to 10 equivalents based on the compound (I). In this step,it is preferable to use a solvent. The kind of the solvent to be usedand the reaction temperature may be the same as those of the case ofusing an amine and an organic acid in step 3. The reaction is generallycompleted within 48 hours.

Step 7

This step is one wherein a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II) is prepared from the2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-halogeno-3-alkylamidopyridinederivative (VII) obtained as the result of step 6 through cyclizationand dehalogenation under reducing conditions. In this step, thereduction and cyclization can be conducted by using the same combinationof a catalyst and a reducing agent as that described in explanation ofstep 3 under the same conditions as those described in explanation ofstep 3.

Step 8

This step is one wherein the2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-halogeno-3-alkylamidopyridinederivative (VII) obtained in step 6 through reductive isomerization iscyclized into a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-halogeno-3H-imidazo[4,5-b]pyridinederivative (VI) under acidic conditions.

This reaction is not limited so far as it is conducted in the presenceof any acid which is used in a conventional organic synthesis. Thereaction is conducted with, for example, specifically, an inorganic acidsuch as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid,hydroiodic acid, perchloric acid, phosphoric acid and polyphosphoricacid; or a sulfonic acid such as methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid and camphorsulfonic acid, under acidicconditions.

This step is also preferably conducted in the presence of a solvent.Specific examples of the solvent include tetrahydrofuran,1,2-dimethoxyethane, diethyl ether, diisopropyl ether, methyl acetate,ethyl acetate, propyl acetate, methyl propionate, ethyl propionate,1,4-dioxane, benzene, toluene, xylene, formic acid, acetic acid,propionic-acid, n-hexane, n-octane and petroleum ether, among whichtetrahydrofuran, 1,2-dimethoxyethane, formic acid, acetic acid,propionic acid, benzene, toluene and xylene are preferable, and formicacid, acetic acid, benzene, toluene and xylene are still preferable. Thesolvent is generally used in an amount of 0.5 to 100 parts by volume,preferably 0.5 to 50 parts by volume, still preferably 1 to 20 parts byvolume based on 1 part by weight of the compound (VIII), though theamount thereof is not limited. The above solvents may be used each aloneor as a mixture of two or more of them.

Further, though the reaction temperature is not particularly limited,the reaction is generally conducted at from 0° C. to the refluxingtemperature of the amine or solvent. Furthermore, in this step, thereaction can be accelerated by removing formed water from the reactionsystem by adding a dehydrating agent such as a molecular sieve or byforming an azeotropic mixture. In such a case, the reaction time isgenerally completed within 12 hours.

Step 9

This step is one wherein an objective2-alkyl-3(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II) is obtained by reductively dehalogenating the2-alkyl-3-(2'-alkoxycarbonylbiphenyl-4-yl)methyl-6-halogeno-3H-imidazo[4,5-b]pyridinederivative (VI) obtained by conducting step 8. This step can beconducted in the same manner as that of step 3.

Step 10

This step is one wherein the2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-halogeno-3-nitropyridinederivative (I) is reductively cyclized without the elimination of thehalogen atom. In this step, reductive cyclization may be conducted bythe use of iron and acetic acid or iron and hydrochloric acid in theconventional manner.

Step 11

The imidazopyridine derivatives which are disclosed in, e.g., JapanesePatent Publication-A Nos. 3-5480, 3-95181, 3-188076 and 3-236377 and areuseful as antagonists against angiotensin II receptor are those having a1H-tetrazol-5-yl group, for example,2-alkyl-3-[{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]-3H-imidazo[4,5-b]pyridines.To obtain these compounds, they can be prepared by converting the cyanogroup of the compound (II) (such as2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine)prepared by the process of the present invention into a 1H-tetrazol-5-ylgroup by, e.g., the process (described in, e.g., Japanese PatentPublication-A No. 3-236377) using sodium azide and ammonium chloride.Among these imidazopyridine derivatives having a tetrazolyl group, onehaving a cyclopropyl group at the 2-position is particularly excellentin the antagonism against angiotensin II receptor and therefore ishighly useful as an antihypertensive drug or a remedy for hemal lesions.The process for the preparation of a2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II) according to the present invention enables theindustrial production of a precursor of such an excellent antagonistagainst angiotensin II receptor.

Then, the 2-alkylamido-5-halogeno-3-nitropyridine derivative (III) ofthe following general formula is a novel compound and is useful as anintermediate for the preparation of the2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II). The objective2-alkyl-3-(2'-cyano-biphenyl-4-yl)-methyl-3H-imidazo[4,5-b]pyridinederivative (II) can be prepared from this intermediate (III) byconducting the above step 2 and then one of step 3, steps 4 and 5, steps6 and 7, steps 10 and 9, and steps 6, 8 and ##STR29##

In the formula, R¹, R² and X are each as defined above. Further specificexamples of the intermediate (III) according to the present inventioninclude the following compounds, though the intermediate (III) is notlimited to them.

(1) 2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine

(2) 2-cyclopropanecarboxamido-5-bromo-4,6-dimethyl-3-nitropyridine

(3) 2-cyclopropanecarboxamido-5-chloro-4-methyl-3-nitropyridine

(4) 2-cyclopropanecarboxamido-5-chloro-4,6-dimethyl-8-nitropyridine

(5) 2-n-butyrylamino-5-bromo-4-methyl-3-nitropyridine

(6) 2-n-butyrylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(7) 2-n-butyrylamino-5-chloro-4-methyl-3-nitropyridine

(8) 2-n-butyrylamino-5-chloro-4,6-dimethyl-3-nitropyridine

(9) 2-n-valerylamino-5-bromo-4-methyl-3-nitropyridine

(10) 2-n-valerylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(11) 2-n-valerylamino-5-chloro-4-methyl-3-nitropyridine

(12) 2-n-valerylamino-5-chloro-4,6-dimethyl-3-nitropyridine

Further, the2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkylamido-5-halogeno-3-nitropyridinederivative (I) of the following general formula is also a novel compoundand is useful as an intermediate for the preparation of theimidazopyridine derivative (II). The objective2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II) can be prepared from the intermediate (I) through one ofstep 3, steps 4 and 5, steps 6 and 7, steps 10 and 9, and steps 6, 8 and9. ##STR30##

In the formula, R¹, R² and X are each as defined above, with the provisothat a case wherein R¹ is a hydrogen atom, R² is a n-butyl group and Xis a bromine atom is excepted. Further specific examples of theintermediate (I) according to the present invention include thefollowing compounds, though the intermediate (I) is not limited to them.

(1)2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine

(2)2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4,6-dimethyl-3-nitropyridine

(3)2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-chloro-4-methyl-3-nitropyridine

(4)2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-chloro-4,6-dimethyl-3-nitropyridine

(5)2-[N-(2'-cyanobiphenyl-4-yl)methyl]butyrylamino--bromo-4-methyl-3-nitropyridine

(6)2-[N-(2'-cyanobiphenyl-4-yl)methyl]butyrylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(7)2-[N-(2'-cyanobiphenyl-4-yl)methyl]butyrylamino-5-chloro-4-methyl-3-nitropyridine

(8)2-[N-(2'-cyanobiphenyl-4-yl)methyl]butyrylamino-5-chloro-4,6-dimethyl-3-nitropyridine

(9)2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-5-bromo-4,6-dimethyl-3-nitropyridine

(10)2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-5-chloro-4-methyl-3-nitropyridine

(11)2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-5-chloro-4,6-dimethyl-3-nitropyridine

Further, the2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-halogeno-3-alkylamidopyridinederivative (VII) of the following general formula is also a novelcompound and is useful as an intermediate for the preparation of theimidazopyridine derivative (II). The objective2-alkyl-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II) can be prepared from this intermediate (VII) througheither the above steps 6 and 7 or the above steps 8 and 9. ##STR31##

In the formula, R¹, R² and X are each as defined above. Further specificexamples of the intermediate (VII) according to the present inventioninclude the following compounds, though the intermediate (VII) is notlimited to them.

(1)3-cyclopropanecarboxamido-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-bromo-4-methylpyridine

(2)3-cyclopropanecarboxamido-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-bromo-4,6-dimethylpyridine

(3)3-cyclopropanecarboxamido-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-chloro-4-methylpyridine

(4)3-cyclopropanecarboxamido-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-chloro-4,6-dimethylpyridine

(5)3-n-butyrylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-bromo-4-methylpyridine

(6)3-n-butyrylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-bromo-4,6-dimethylpyridine

(7)3-n-butyrylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-chloro-4-methylpyridine

(8)3-n-butyrylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-chloro-4,6-dimethylpyridine

(9)3-n-valerylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-bromo-4-methylpyridine

(10)3-n-valerylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-bromo-4,6-dimethylpyridine

(11)3-n-valerylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-chloro-4-methylpyridine

(12)3-n-valerylamino-2-[N-(2'-cyanobiphenyl-4-yl)methyl]amino-5-chloro-4,6-dimethylpyridine

Compounds in which R¹ is a hydrogen atom and the --CN is present at the2'-position of the biphenyl in the above description and the applicationof the process of the present invention to the preparation of suchcompounds are particularly preferable.

Then, the present inventors have extensively studied to find an activebiphenyl intermediate improved on the above disadvantages. As a result,they have found that a biphenyloxazoline derivative (I) represented bythe following general formula which is a novel compound is an excellentindustrial intermediate satisfying the above requirements, and haveaccomplished the present invention: ##STR32##

In the formula, R¹ represents a hydroxyl group, a lower alkylsulfonyloxygroup, an arylsulfonyloxy group or a halogen atom.

The biphenyloxazoline derivative (I) according to the present inventioncan be prepared by any of the following processes.

(1) protecting 4-bromobenzyl alcohol to form a 4-bromobenzyl etherderivative (V), coupling it with oxazolylanisole to form analkoxymethyl-biphenyloxazoline derivative (IV) through the Grignardreaction, eliminating the protective group to form ahydroxymethyl-biphenyloxazoline derivative (II), and then conductingsulfonylation or halogenation.

(2) oxidizing a methyl-biphenyloxazoline derivative (VIII) to form acarboxy-biphenyloxazoline derivative (VII), either esterifying it with alower alcohol and then reducing it with a metal hydride complex orreducing it with a metal hydride complex to form ahydroxymethyl-biphenyloxazoline derivative (II), and then conductingsulfonylation or halogenation.

The outline of the reaction path according to the present invention isrepresented by the following chemical reaction scheme (reactionscheme-6): ##STR33##

Accordingly, an object of the present invention is to provide abiphenyloxazoline derivative (I) which is an active intermediate usefulfor introducing the side chain of biphenyl in the preparation of a2-alkyl-3-(2'-alkoxycarbonylbiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative which is an antagonist against angiotensin II receptor usefulas an antihypertensive drug or a remedy for hemal lesions, a process forthe preparation thereof, and further an intermediate useful for thepreparation thereof.

The biphenyloxazoline derivative (I) according to the present inventionhas the following general formula: ##STR34##

In the formula, R¹ represents a hydroxyl group, a lower alkylsulfonyloxygroup, an arylsulfonyloxy group or a halogen atom. Specific examples ofthe lower alkylsulfonyloxy group include those having a lower alkylgroup of 1 to 6 carbon atoms, such as a methanesulfonyloxy group and anethanesulfonyloxy group; those of the arylsulfonyloxy group include abenzenesulfonyloxy group and a toluenesulfonyloxy group; and those ofthe halogen atom include a chlorine atom, a bromine atom, an iodine atomand a fluorine atom.

Further, specific examples of the biphenyloxazoline derivative (I)include the following compounds, though the biphenyloxazoline derivative(I) according to the present invention is not limited to them.

(1) 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-(4'-chloromethyl-biphenyl-2-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-bromomethyl-biphenyl-2-yl)oxazoline

(4) 4,4-dimethyl-2-(4'-iodomethyl-biphenyl-2-yl)oxazoline

(5) 4,4-dimethyl-2-(4'-methanesulfonyloxymethyl-biphenyl-2-yl)oxazoline

(6) 4,4-dimethyl-2-(4'-ethanesulfonyloxymethyl-biphenyl-2-yl)oxazoline

(7) 4,4-dimethyl-2-(4'-p-toluenesulfonyloxymethylphenyl-2-yl)oxazoline

(8) 4,4-dimethyl-2-(4'-benzenesulfonyloxymethylphenyl-2-yl)oxazoline

Then, the hydroxymethyl-biphenyloxazoline derivative (II) according tothe present invention has the following general formula: ##STR35##

Specific examples thereof include the following compounds.

(1) 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-3-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-4-yl)oxazoline

Then, the active biphenyloxazoline derivative (III) has the followingchemical structural formula: ##STR36##

In the formula, R² represents a lower alkylsulfonyloxy group, anarylsulfonyloxy group or a halogen atom. Specific examples of thesegroups include the same groups as those described above.

Further specific examples of the active biphenyloxazoline derivative(III) include the following compounds, though the activebiphenyloxazoline derivative (III) according to the present invention isnot limited to them.

(1) 4,4-dimethyl-2-(4'-chloromethyl-biphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-(4'-bromomethyl-biphenyl-2-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-iodomethyl-biphenyl-2-yl)oxazoline

(4) 4,4-dimethyl-2-(4'-methanesulfonyloxymethyl-biphenyl-2-yl)oxazoline

(5) 4,4-dimethyl-2-(4'-ethanesulfonyloxymethyl-biphenyl-2-yl)oxazoline

(6)4,4-dimethyl-2-(4'-p-toluenesulfonyloxymethyl-biphenyl-2-yl)oxazoline

(7) 4,4-dimethyl-2-(4'-benzenesulfonyloxymethylphenyl-2-yl)oxazoline

Further, the alkoxymethyl-biphenyloxazoline derivative (IV) according tothe present invention has the following chemical structural formula:##STR37##

In the formula, R³ represents a lower alkoxyalkyl group, an aryloxyalkylgroup, an aralkyloxyalkyl group, a lower alkoxyalkoxyalkyl group, alower thioalkoxyalkyl group, a cycloether group, a trialkylsilyl group,a triarylsilyl group, a lower alkyl group, a vinyl group, an aralkylgroup or a triphenylmethyl group.

Further specific examples of the lower alkoxyalkyl group include amethoxymethyl group, an ethoxymethyl group, a propoxymethyl group, amethoxyethyl group, an ethoxyethyl group, a propoxyethyl group and apropoxypropyl group; those of the aryloxyalkyl group include aphenoxymethyl group, a phenoxyethyl group and a tolyloxymethyl group;those of the aralkyloxyalkyl group include a benzyloxymethyl group and aphenethyloxymethyl group; those of the lower alkoxyalkoxyalkyl groupinclude a methoxyethoxymethyl group and an ethoxyethoxymethyl group;those of the lower thioalkoxyalkyl group include a methylthiomethylgroup, a methylthioethyl group, an ethylthiomethyl group, aphenylthiomethyl group and a benzylthiomethyl group; those of thecycloether group include a tetrahydropyranyl group and atetrahydrofuranyl group; those of the trialkylsilyl group include atrimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilylgroup, an i-propyldimethylsilyl group and a phenyldimethylsilyl group;that of the triarylsilyl group includes a triphenylsilyl group; those ofthe lower alkyl group include a methyl group, an ethyl group, a propylgroup and a t-butyl group; and those of the aralkyl group include abenzyl group, a phenethyl group, a methylbenzyl group, a trimethylbenzylgroup, a nitrobenzyl group and a phenacyl group.

Further, specific and representative examples of thealkoxymethyl-biphenyloxazoline derivative (IV) include the followingcompounds, though the alkoxymethyl-biphenyloxazoline derivative (IV)according to the present invention is not limited to them.

(1) 4,4-dimethyl-2-(4'-methoxymethoxymethyl-biphenyl-2-yl)oxazoline

(2)4,4-dimethyl-2-(4'-methoxyethoxymethoxymethyl-biphenyl-2-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-thiomethoxymethoxymethyl-biphenyl-2-yl)oxazoline

(4)4,4-dimethyl-2-(4'-tetrahydropyranyloxymethyl-biphenyl-2-yl)oxazoline

(5)4,4-dimethyl-2-(4'-tetrahydrofurabyloxymethyl-biphenyl-2-yl)oxazoline

(6) 4,4-dimethyl-2-(4'-trimethylsilyloxymethyl-biphenyl-2-yl)oxazoline

(7) 4,4-dimethyl-2-(4'-t-butoxymethyl-biphenyl-2-yl)oxazoline

(8) 4,4-dimethyl-2-(4'-benzyloxymethyl-biphenyl-2-yl)oxazoline

Further, the 4-bromobenzyl ether derivative (V) according to the presentinvention has the following chemical structural formula: ##STR38##

In the formula, R³ is as defined above. Further specific examples of the4-bromobenzyl ether derivative (V) include the following compounds,though the 4-bromobenzyl ether derivative (V) according to the presentinvention is not limited to them.

(1) 4-bromobenzyl-methoxymethyl ether

(2) 4-bromobenzyl-methoxyethoxymethyl ether

(3) 4-bromobenzyl-thiomethoxymethyl ether

(4) 4-bromobenzyl-tetrahydropyranyl ether

(5) 4-bromobenzyl-tetrahydrofuranyl ether

(6) 4-bromobenzyl-trimethylsilyl ether

(7) 4-bromobenzyl-t-butyl ether

(8) 4-bromobenzyl-benzyl ether

Further, the alkoxycarbonyl-biphenyloxazoline derivative (VI) accordingto the present invention has the following chemical structural formula:##STR39##

In the formula, R⁴ represents a lower alkyl group, an aryl group, anaralkyl group, a cycloether group, a trialkylsilyl group, a triarylsilylgroup, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group,an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethylgroup. It is preferable that R⁴ be a lower alkyl group, an aryl group,an aralkyl group, a cycloether group, a triarylsilyl group, a vinylgroup, a lower alkoxyalkyl group, an aryloxyalkyl group, anaralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethylgroup. Specific examples of the lower alkyl group include groups having1 to 6 carbon atoms such as a methyl group, an ethyl group, a propylgroup, a butyl group, a pentyl group and a hexyl group; those of thearyl group include a phenyl group, a tolyl group and a xylyl group;those of the aralkyl group include a benzyl group and a phenethyl group;those of the cycloether group include a tetrahydropyranyl group and atetrahydrofuranyl group; those of the triarylsilyl group include atrimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilylgroup, an 1-propyldimethylsilyl group and a phenyldimethylsilyl group;those of the lower alkoxyalkyl group include a methoxymethyl group, anethoxymethyl group, a propoxymethyl group, a methoxyethyl group, anethoxyethyl group, a propoxyethyl group and a propoxypropyl group; thoseof the aryloxyalkyl group include a phenoxymethyl group, a phenoxyethylgroup and a tolyloxymethyl group; those of the aralkyloxyalkyl groupinclude a bonzyloxymethyl group and a phenethyloxymethyl group; andthose of the thioalkoxyalkyl group include a methylthiomethyl group, amethylthioethyl group, an ethylthiomethyl group, a phenylthiomethylgroup and a benzylthiomethyl group. Further specific examples of thealkoxycarbonylbiphenyloxazoline derivative (VI) include the followingcompounds, though the alkoxycarbonylbiphenyloxazoline derivative (VI)according to the present invention is not limited to them.

(1) 4,4-dimethyl-2-(4'-methoxycarbonylbiphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-(4'-ethoxycarbonylbiphenyl-2-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-propoxycarbonylbiphenyl-2-yl)oxazoline

(4) 4,4-dimethyl-2-(4'-phenoxycarbonylbiphenyl-2-yl)oxazoline

(5) 4,4-dimethyl-2-(4'-benzyloxycarbonylbiphenyl-2yl)oxazoline

(6)4,4-dimethyl-2-(4'-tetrahydropyranyloxycarbonylbiphenyl-2-yl)oxazoline

Further, the carboxy-biphenyloxazoline derivative (VII) according to thepresent invention has the following chemical structural formula:##STR40##

Specific and representative examples of the carboxy-biphenyloxazolinederivative (VII) according to the present invention include thefollowing compounds, though the derivative (VII) is not limited to them.

(1) 4,4-dimethyl-2-(4'-carboxybiphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-(4'-carboxybiphenyl-3-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-carboxybiphenyl-4-yl)oxazoline

Further, the methyl-biphenyloxazoline derivative (VIII) according to thepresent invention has the following chemical structural formula:##STR41##

Specific and representative examples of the methyl-biphenyloxazolinederivative (VIII) according to the present invention include thefollowing compounds, though the derivative (VIII) is not limited tothem.

(1) 4,4-dimethyl-2-(4'-methyl-biphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-(4'-methyl-biphenyl-3-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-methyl-biphenyl-4-yl)oxazoline

Next, each step of the process according to the present invention willbe described in detail hereinafter (see the above reaction scheme-6).

Step 1

This step is one wherein 4-bromobenzyl alcohol is protected to obtain a4-bromobenzyl ether derivative (V). This step can be conducted accordingto the conventional process for introducing a protective group for ahydroxyl group in organic synthesis. Specific examples of the reagentfor introducing a protective group usable in this step includechloromethyl methyl ether, 2-chloroethyl methyl ether, chloromethylphenyl ether, chloromethyl benzyl ether, chloromethyl methoxyethylether, chloromethyl methyl sulfide, dihydropyrane, dihydrofuran,chlorotrimethylsilane, chlorotriethylsilane, chlorotriphenylsilane,methyl iodide, benzyl chloride and chlorotriphenylmethane.

Step 2

This step is one wherein the 4-bromobenzyl ether derivative (V) iscoupled with oxazolylanisole to form an alkoxymethyl-biphenyloxazolinederivative (IV) through the Grignard reaction. This reaction can beconducted by the conventional process for the Grignard reaction asdescribed in, e.g., Journal of Organic Chemistry (J. Org. Chem.), 43(7), 1372 to 1379, 1978.

Step 3

In this step, the protective group of the alkoxymethyl-biphenyloxazolinederivative (IV) is eliminated to form a hydroxymethyl-biphenyloxazolinederivative (II). This reaction can be conducted according to a commonprocess for eliminating the protective group such as hydrolysis andcatalytic reduction.

Step 4

Step 4 is one wherein a methyl-biphenyloxazoline derivative (VIII) isoxidized into a carboxy-biphenyloxazoline derivative (VII). In thisreaction, an oxidizing agent is used, and specific examples thereofusable in this reaction include permanganates, chromium oxide andbichromates, among which permanganates are preferable. This reaction canbe conducted according to the process described in, e.g., OrganicSynthesis, Col. Vol. II, 135. In the present invention, themethyl-biphenyloxazoline derivative (VIII) is dissolved in a solvent, apermanganate such as potassium permanganate is added thereto, and theobtained mixture is heated.

Although the amount of the permanganate used is not limited, it isgenerally used in an amount of about 1 to 100 equivalents, morepreferably about 2 to 50 equivalents, still preferably about 3 to 20equivalents per equivalent of the methyl-biphenyloxazoline derivative(VIII).

The solvent to be used in this reaction is not limited, so far as it isinert to the methyl-biphenyloxazoline derivative (VIII) or the oxidizingagent. Specific examples thereof include water, pyridine, formic acidand acetic acid. The solvent may be used either alone or as a mixture oftwo or more of them. Although the amount of the solvent used is notlimited, it is generally used in an amount of about 0.5 to 100 parts byvolume, more preferably about 0.5 to 50 parts by volume, stillpreferably about 1 to 20 parts by volume based on 1 part by weight ofthe methyl-biphenyloxazoline derivative (VIII).

This reaction is generally conducted under heating at a temperatureranging from 50° C. to the refluxing temperature of the solvent.Although the reaction time varies depending upon the kind or amount ofthe oxidizing agent, temperature or the like, it is generally completedin about 1 to 48 hours.

Steps 5 and 7

These steps are those wherein the carboxy-biphenyloxazoline derivative(VII) or the alkoxycarbonyl-biphenyloxazoline derivative (VI) is reducedwith a metal hydride complex into a hydroxymethyl-biphenyloxazolinederivative (II). Specific examples of the metal hydride complex in thepresent invention include aluminum lithium hydride,bis(2-methoxyethoxy)aluminum sodium hydride, diisobutylaluminum hydrideand diborane. Although the amount of the metal hydride complex used isnot limited, it is generally used in an amount of about 0.2 to 50equivalents, more preferably about 0.5 to 20 equivalents, stillpreferably about 1 to 10 equivalents per equivalent of thecarboxy-biphenyloxazoline derivative (VII) or thealkoxycarbonyl-biphenyloxazoline derivative (VI).

It is preferable to use a solvent in this reaction. The solvent usableis not limited, so far as it is inert to the carboxy-biphenyloxazolinederivative (VII) or the alkoxycarbonyl-biphenyloxazoline derivative(VI), or the metal hydride complex. Specific examples thereof includetetrahydrofuran, 1,2-dimethoxyethane, ethyl ether, isopropyl ether,2-methoxyethyl ether, dioxane, dioxolane, benzene, toluene, hexane andoctane. The solvent may be used either alone or as a mixture of two ormore of them. Although the amount of the solvent used is not limited, itis generally used in an amount of about 0.5 to 100 parts by volume, morepreferably about 0.5 to 50 parts by volume, still preferably about 1 to20 parts by volume based on 1 part by weight of thecarboxy-biphenyloxazoline derivative (VII) or thealkoxycarbonyl-biphenyloxazoline derivative (VI).

Although this reaction can be generally conducted at a temperatureranging from -70° C. to the refluxing temperature of the solvent, it isgenerally conducted under cooling with ice. Although the reaction timevaries depending upon the kind or amount of the metal hydride complex,temperature or the like, it is generally completed in about 5 minutes to6 hours.

Step 6

This step is one wherein the carboxy-biphenyloxazoline derivative (VII)obtained in step 4 is esterified into analkoxycarbonyl-biphenyloxazoline derivative (VI). This reaction can beconducted according to the common esterification process.

Step 8

This step is one wherein an active biphenyloxazoline derivative (III) isprepared through the sulfonylation or halogenation of thehydroxymethyl-biphenyloxazoline derivative (II).

The sulfonylation is conducted according to the conventional processwith a reagent for sulfonylation such as methanesulfonyl chloride,ethanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonylchloride. Although the amount of the reagent for sulfonylation used isnot limited, it is generally used in an amount of about 1 to 50equivalents, more preferably about 1.2 to 20 equivalents, stillpreferably 1.5 to 10 equivalents per equivalent of thehydroxymethyl-biphenyloxazoline derivative (II).

On the other hand, the halogenation is conducted according to theconventional process with a reagent for halogenation such ashydrochloric acid, thionyl chloride, sulfuryl chloride, phosphorustrichloride, phosphorus pentachloride, phosphorus oxychloride, oxalylchloride, phosgene, diphosgene, triphosgene, hydrobromic acid, thionylbromide and phosphorus tribromide. Although the amount of the reagentfor halogenation used is not limited, it is generally used in an amountof about 1 to 50 equivalents, more preferably about 1.5 to 20equivalents, still preferably about 2 to 10 equivalents per equivalentof the hydroxymethyl-biphenyloxazoline derivative (II).

The active biphenyloxazoline derivative (III) according to the presentinvention is highly stable and can be further purified by an ordinarymethod such as silica gel column chromatography and vacuum distillation.

Then, a 4-substituted biphehyloxazoline derivative (IX) represented bythe following general formula is a novel compound and is useful as anintermediate for the preparation of the biphenyloxazoline derivative (I)according to the present invention: ##STR42##

In the formula, R⁵ represents a carboxyl group, a lower alkoxycarbonylgroup, a lower alkoxyalkoxymethyl group, an aryloxyalkoxymethyl group,an aralkyloxyalkoxymethyl group, a lower alkoxyalkoxyalkoxymethyl group,a lower thioalkoxyalkoxymethyl group, a cycloetheroxymethyl group, atrialkylsilyloxymethyl group, a triarylsilyloxymethyl group, a loweralkoxymethyl group, a vinyloxymethyl group, an aralkyloxymethyl group ora triphenylmethoxymethyl group.

As specific examples of the substituent of R⁵, those of the loweralkoxycarbonyl group include groups having an alkyl group of 1 to 6carbon atoms in the molecule, such as a methoxycarbonyl group, anethoxycarbonyl group and a propoxycarbonyl group; those of the loweralkoxyalkoxymethyl group include a methoxymethoxymethyl group, anethoxymethoxymethyl group, a propoxymethoxymethyl group, amethoxyethoxymethyl group, an ethoxyethoxymethyl group, apropoxyethoxymethyl group and a propoxypropoxymethyl group; those of thearyloxyalkoxymethyl group include a phenoxymethoxymethyl group, aphenoxyethoxymethyl group and a tolyloxymethoxymethyl group; those ofthe aralkyloxyalkoxymethyl group include a benzyloxymethoxymethyl groupand a phenethyloxymethoxymethyl group; those of the loweralkoxyalkoxyalkoxymethyl group include a methoxyethoxymethoxymethylgroup and an ethoxyethoxymethoxymethyl group; those of the lowerthioalkoxyalkoxymethyl group include a methylthiomethoxymethyl group, amethylthioethoxymethyl group, an ethylthiomethoxymethyl group, aphenylthiomethoxymethyl group and a benzylthiomethoxymethyl group; thoseof the cycloetheroxymethyl group include a tetrahydropyranyloxymethylgroup and a tetrahydrofuranyloxymethyl group; those of thetrialkylsilyloxymethyl group include a trimethylsilyloxymethyl group, atriethylsilyloxymethyl group, a t-butyldimethylsilyloxymethyl group, ani-propyldimethylsilyloxymethyl group and a phenyldimethylsilyloxymethylgroup; that of the triarylsilyloxymethyl group includes atriphenylsilyloxymethyl group; those of the lower alkoxymethyl groupinclude a methoxymethyl group, an ethoxymethyl group, a propoxymethylgroup and a t-butoxymethyl group; and those of the aralkyloxymethylgroup include a benzyloxymethyl group, a phenethyloxymethyl group, amethylbenzyloxymethyl group, a trimethylbenzyloxymethyl group, anitrobenzyloxymethyl group and a phenacyloxymethyl group.

Further specific and representative examples of the 4-substitutedbiphenyloxazoline derivative (IX) include the following compounds,though the 4substituted biphenyloxazoline derivative (IX) according tothe present invention is not limited to them.

(1) 4,4-dimethyl-2-(4'-methoxymethoxymethyl-biphenyl-2-yl)oxazoline

(2)4,4-dimethyl-2-(4'-methoxyethoxymethoxymethyl-biphenyl-2-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-thiomethoxymethoxymethyl-biphenyl-2-yl)oxazoline

(4)4,4-dimethyl-2-(4'-tetrahydropyranyloxymethyl-biphenyl-2-yl)oxazoline

(5)4,4-dimethyl-2-(4'-tetrahydrofuranyloxymethyl-biphenyl-2-yl)oxazoline

(6) 4,4-dimethyl-2-(4'-trimethylsilyloxymethyl-biphenyl-2-yl)oxazoline

(7) 4,4-dimethyl-2-(4'-t-butoxymethyl-biphenyl-2-yl)oxazoline

(8) 4,4-dimethyl-2-(4'-benzyloxymethyl-biphenyl-2-yl)oxazoline

(9) 4,4-dimethyl-2-(4'-carboxybiphenyl-2-yl)oxazoline

(10) 4,4-dimethyl-2-(4'-carboxybiphenyl-3-yl)oxazoline

(11) 4,4-dimethyl-2-(4'-carboxybiphenyl-4-yl)oxazoline

(12) 4,4-dimethyl-2-(4'-methoxycarbonylbiphenyl-2yl)oxazoline

(13) 4,4-dimethyl-2-(4'-ethoxycarbonylbiphenyl-2-yl)oxazoline

(14) 4,4-dimethyl-2-(4'-propoxycarbonylbiphenyl-2yl)oxazoline

(15) 4,4-dimethyl-2-(4'-phenoxycarbonylbiphenyl-2yl)oxazoline

(16) 4,4-dimethyl-2-(4'-benzyloxycarbonylbiphenyl-2yl)oxazoline

(17)4,4-dimethyl-2-(4'-tetrahydropyranyloxycarbonylbiphenyl-2-yl)oxazoline

Then, the present inventors have extensively studied to find an activebiphenyl intermediate improved in the above disadvantages. As a result,they have found that a sulfonyloxy-biphenylcarboxylic ester derivative(I) of the following general formula which is a novel compound is anexcellent industrial intermediate satisfying the above requirements, andhave accomplished the present invention: ##STR43##

In the formula, R¹ represents a lower alkylsulfonyloxy group or anarylsulfonyloxy group; and R² represents a lower alkyl group, an arylgroup, an aralkyl group, a cycloether group, a triarylsilyl group, avinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, anaralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethylgroup.

The sulfonyloxy-biphenylcarboxylic ester derivative (I) according to thepresent invention can be prepared by any of the following processes.

(1) protecting 4-bromobenzyl alcohol to form a 4-bromobenzyl etherderivative (VI), coupling it with oxazolylanisole to form analkoxymethyl-biphenyloxazoline derivative (V) through the Grignardreaction, eliminating the protective group to form ahydroxymethyl-biphenyloxazoline derivative (IV), eliminating theprotective group to form a hydroxymethyl-biphenylcarboxylic acidderivative (III), esterifying it into a hydroxymethyl-biphenylcarboxylicester derivative (II), and then conducting sulfonylation.

(2) oxidizing a methyl-biphenyloxazoline derivative (IX) with anoxidizing agent into a carboxy-biphenyloxazoline derivative (VII),either esterifying it with a lower alcohol into analkoxycarbonyl-biphenyloxazoline derivative (VIII) and then reducing itwith a metal hydride complex or directly reducing it with a metalhydride complex to form a hydroxymethyl-biphenyloxazoline derivative(IV), eliminating the protective group to form ahydroxymethyl-biphenylcarboxylic acid derivative (III), esterifying itinto a hydroxymethyl-biphenylcarboxylic ester derivative (II) and,further, conducting sulfonylation.

The outline of the reaction path according to the present invention isrepresented by the following chemical reaction scheme (reactionscheme-7). ##STR44##

Accordingly, an object of the present invention is to provide asulfonyloxy-biphenylcarboxylic ester derivative (I) which is an activeintermediate useful for introducing the side chain of biphenyl in thepreparation of a2-alkyl-3-(2'-alkoxycarbonylbiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative which is an antagonist against angiotensin II receptor usefulas an antihypertensive drug and a remedy for hemal lesions, a processfor the preparation thereof, and an intermediate useful for thepreparation thereof.

The sulfonyloxy-biphenylcarboxylic ester derivative (I) according to thepresent invention has the following general formula: ##STR45##

In the formula, R¹ represents a lower alkylsulfonyloxy group or anarylsulfonyloxy group; and R² represents a lower alkyl group, an arylgroup, an aralkyl group, a cycloether group, a triarylsilyl group, avinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group, anaralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethylgroup. Specific examples of the lower alkylsulfonyloxy group of R¹include groups having an alkyl group of 1 to 6 carbon atoms in themolecule, such as a methanesulfonyloxy group and an ethanesulfonyloxygroup; and those of the arylsulfonyloxy group include abenzenesulfonyloxy group and a toluenesulfonyloxy group. Further,specific examples of the lower alkyl group of R² include groups having 1to 6 carbon atoms, such as a methyl group, an ethyl group, a n-propylgroup, an i-propyl group, a n-butyl group, an i-butyl group, a t-butylgroup, a pentyl group and a hexyl group; those of the aryl group includea phenyl group, a tolyl group and a xylyl group; those of the aralkylgroup include a benzyl group and a phenethyl group; those of thecycloether group include a tetrahydropyranyl group and atetrahydrofuranyl group; those of the triarylsilyl group include atrimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilylgroup, an i-propyldimethylsilyl group and a phenyldimethylsilyl group;those of the lower alkoxyalkyl group include a methoxymethyl group, anethoxymethyl group, a propoxymethyl group, a methoxyethyl group, anethoxyethyl group, a propoxyethyl group and a propoxypropyl group; thoseof the aryloxyalkyl group include a phenoxymethyl group, a phenoxyethylgroup and a tolyloxymethyl group; those of the aralkyloxyalkyl groupinclude a benzyloxymethyl group and a phenethyloxymethyl group; andthose of the thioalkoxyalkyl group include a methylthiomethyl group, amethylthioethyl group, an ethylthiomethyl group, a phenylthiomethylgroup and a benzylthiomethyl group.

Further specific examples of the sulfonyloxybiphenylcarboxylic esterderivative (I) include the following compounds, though thesulfonyloxy-biphenylcarboxylic ester derivative (I) according to thepresent invention is not limited to them.

(1) methyl 2-(4'-methanesulfonyloxymethylphenyl)benzoate

(2) methyl 3-(4'-methanesulfonyloxymethylphenyl)benzoate

(3) methyl 4-(4'-methanesulfonyloxymethylphenyl)benzoate

(4) ethyl 2-(4'-methanesulfonyloxymethylphenyl)benzoate

(5) ethyl 3-(4'-methanesulfonyloxymethylphenyl)benzoate

(6) ethyl 4-(4'-methanesulfonyloxymethylphenyl)benzoate

(7) methyl 2-(4'-ethanesulfonyloxymethylphenylbenzoate

(8) methyl 3-(4'-ethanesulfonyloxymethylphenyl)benzoate

(9) methyl 4-(4'-ethanesulfonyloxymethylphenyl)benzoate

(10) ethyl 2-(4'-ethanesulfonyloxymethylphenyl)benzoate

(11) ethyl 3-(4'-ethanesulfonyloxymethylphenyl)benzoate

(12) ethyl 4-(4'-ethanesulfonyloxymethylphenyl)benzoate

(13) methyl 2-(4'-p-toluenesulfonyloxymethylphenyl)benzoate

(14) methyl 3-(4'-p-toluenesulfonyloxymethylphenyl)benzoate

(15) methyl 4-(4'-p-toluenesulfonyloxymethylphenyl)benzoate

(16) ethyl 2-(4'-p-toluenesulfonyloxymethylphenyl)benzoate

(17) ethyl 3-(4'-p-toluenesulfonyloxymethylphenyl)benzoate

(18) ethyl 4-(4'-p-toluenesulfonyloxymethylphenyl)benzoate

(19) methyl 2-(4'-benzenesulfonyloxymethylphenyl)benzoate

(20) methyl 3-(4'-benzenesulfonyloxymethylphenyl)benzoate

(21) methyl 4-(4'-benzenesulfonyloxymethylphenyl)benzoate

(22) ethyl 2-(4'-benzenesulfonyloxymethylphenyl)benzoate

(23) ethyl 3-(4'-benzenesulfonyloxymethylphenyl)benzoate

(24) ethyl 4-(4'-benzenesulfonyloxymethylphenyl)benzoate

Then, the hydroxymethyl-biphenylcarboxylic ester derivative (II)according to the present invention has the following general formula:##STR46##

In the formula, R² is as defined above. Specific examples of thehydroxymethyl-biphenylcarboxylic ester derivative (II) according to thepresent invention include the following compounds, though the derivative(II) is not limited to them.

(1) methyl 2-(4'-hydroxymethylphenyl)benzoate

(2) methyl 3-(4'-hydroxymethylphenyl)benzoate

(3) methyl 4-(4'-hydroxymethylphenyl)benzoate

(4) ethyl 2-(4'-hydroxymethylphenyl)benzoate

(5) ethyl 3-(4'-hydroxymethylphenyl)benzoate

(6) ethyl 4-(4'-hydroxymethylphenyl)benzoate

Then, the hydroxymethyl-biphenylcarboxylic acid derivative (III) has thefollowing chemical structural formula: ##STR47##

Further specific examples of the hydroxymethyl-biphenylcarboxylic acidderivative (III) include the following compounds, though thehydroxymethyl-biphenylcarboxylic acid derivative (III) according to thepresent invention is not limited to them.

(1) 2-(4'-hydroxymethylphenyl)benzoic acid

(2) 3-(4'-hydroxymethylphenyl)benzoic acid

(3) 4-(4'-hydroxymethylphenyl)benzoic acid

Further, the hydroxymethyl-biphenyloxazoline derivative (IV) accordingto the present invention has the following chemical structural formula:##STR48##

Further specific examples of the hydroxymethyl-biphenyloxazolinederivative (IV) according to the present invention include the followingcompounds, though the derivative (IV) is not limited to them.

(1) 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-3-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-4-yl)oxazoline

Then, the alkoxymethyl-biphenyloxazoline derivative (V) has thefollowing chemical structural formula: ##STR49##

In the formula, R³ represents a lower alkoxyalkyl group, an aryloxyalkylgroup, an aralkyloxyalkyl group, a lower alkoxyalkoxyalkyl group, athioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, atriarylsilyl group, a lower alkyl group, a vinyl group, an aralkyl groupor a triphenylmethyl group.

Further specially, examples of the lower alkoxyalkyl group include amethoxymethyl group, an ethoxymethyl group, a propoxymethyl group, amethoxyethyl group, an ethoxyethyl group, a propoxyethyl group and apropoxypropyl group; those of the aryloxyalkyl group include aphenoxymethyl group, a phenoxyethyl group and a tolyloxymethyl group;those of the aralkyloxyalkyl group include a benzyloxymethyl group and aphenethyloxymethyl group; those of the lower alkoxyalkoxyalkyl groupinclude a methoxyethoxymethyl group and an ethoxyethoxymethyl group;those of the thioalkoxyalkyl group include a methylthiomethyl group, amethylthioethyl group, an ethylthiomethyl group, a phenylthiomethylgroup and a benzylthiomethyl group; those of the cycloether groupinclude a tetrahydropyranyl group and a tetrahydrofuranyl group; thoseof the trialkylsilyl group include a trimethylsilyl group, atriethylsilyl group, a t-butyldimethylsilyl group, ani-propyldimethylsilyl group and a phenyldimethylsilyl group; that of thetriarylsilyl group includes a triphenylsilyl group; those of the loweralkyl group include a methyl group, an ethyl group, a propyl group and at-butyl group; and those of the aralkyl group include a benzyl group, aphenethyl group, a methylbenzyl group, a trimethylbenzyl group, anitrobenzyl group and a phenacyl group.

Further, specific and representative examples of thealkoxymethyl-biphenyloxazoline derivative (V) include the followingcompounds, though the alkoxymethyl-biphenyloxazoline derivative (V)according to the present invention is not limited to them.

(1) 4,4-dimethyl-2-(4'-methoxymethoxymethyl-biphenyl-2-yl)oxazoline

(2)4,4-dimethyl-2-(4'-methoxyethoxymethoxymethyl-biphenyl-2-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-thiomethoxymethoxymethyl-biphenyl-2-yl)oxazoline

(4)4,4-dimethyl-2-(4'-tetrahydropyranyloxymethyl-biphenyl-2-yl)oxazoline

(5)4,4-dimethyl-2-(4'-tetrahydrofuranyloxymethyl-biphenyl-2-yl)oxazoline

(6) 4,4-dimethyl-2-(4'-trimethylsilyloxymethyl-biphenyl-2-yl)oxazoline

(7) 4,4-dimethyl-2-(4'-t-butoxymethyl-biphenyl-2yl)oxazoline

(8) 4,4-dimethyl-2-(4'-benzyloxymethyl-biphenyl-2yl)oxazoline

Further, the 4-bromobenzyl ether derivative (VI) according to thepresent invention has the following chemical structural formula:##STR50##

In the formula, R³ is as defined above. Further specific examples of the4-bromobenzyl ether derivative (VI) include the following compounds,though the 4-bromobenzyl ether derivative (VI) according to the presentinvention is not limited to them.

(1) 4-bromobenzyl-methoxymethyl ether

(2) 4-bromobenzyl-methoxyethoxymethyl ether

(3) 4-bromobenzyl-thiomethoxymethyl ether

(4) 4-bromobenzyl-tetrahydropyranyl ether

(5) 4-bromobenzyl-tetrahydrofuranyl ether

(6) 4-bromobenzyl-trimethylsilyl ether

(7) 4-bromobenzyl-t-butyl ether

(8) 4-bromobenzyl-benzyl ether

Further, the carboxy-biphenyloxazoline derivative (VII) according to thepresent invention has the following chemical structural formula:##STR51##

Further specific examples of the carboxybiphenyloxazoline derivative(VII) according to the present invention include the followingcompounds, though the derivative (VII) is not limited to them.

(1) 4,4-dimethyl-2-(4'-carboxybiphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-(4'-carboxybiphenyl-3-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-carboxybiphenyl-4-yl)oxazoline

Further, the alkoxycarbonyl-biphenyloxazoline derivative (VIII)according to the present invention has the following chemical structuralformula: ##STR52##

In the formula, R⁴ represents a lower alkyl group, an aryl group, anaralkyl group, a cycloether group, a trialkylsilyl group, a triarylsilylgroup, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group,an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethylgroup. It is preferable that R⁴ be a lower alkyl group, an aryl group,an aralkyl group, a cycloether group, a triarylsilyl group, a vinylgroup, a lower alkoxyalkyl group, an aryloxyalkyl group, anaralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethylgroup. Specific examples of the lower alkyl group include groups having1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propylgroup, a butyl group, a pentyl group and a hexyl group; those of thearyl group include a phenyl group, a tolyl group and a xylyl group;those of the aralkyl group include a benzyl group and a phenethyl group;those of the cycloether group include a tetrahydropyranyl group and atetrahydrofuranyl group; those of the triarylsilyl group include atrimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilylgroup, an i-propyldimethylsilyl group and a phenyldimethylsilyl group;those of the lower alkoxyalkyl group include a methoxymethyl group, anethoxymethyl group, a propoxymethyl group, a methoxyethyl group, anethoxyethyl group, a propoxyethyl group and a propoxypropyl group; thoseof the aryloxyalkyl group include a phenoxymethyl group, a phenoxyethylgroup and a tolyloxymethyl group; those of the aralkyloxyalkyl groupinclude a benzyloxymethyl group and a phenethyloxymethyl group; andthose of the thioalkoxyalkyl group include a methylthiomethyl group, amethylthioethyl group, an ethylthiomethyl group, a phenylthiomethylgroup and a benzylthiomethyl group. Further specific examples of thealkoxycarbonylbiphenyloxazoline derivative (VIII) include the followingcompounds, though the alkoxycarbonylbiphenyloxazoline derivative (VIII)according to the present invertion is not limited to them.

(1) 4,4-dimethyl-2-(4'-methoxycarbonylbiphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-(4'-ethoxycarbonylbiphenyl-2-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-propoxycarbonylbiphenyl-2-yl)oxazoline

(4) 4,4-dimethyl-2-(4'-phenoxycarbonylbiphenyl-2-yl)oxazoline

(5) 4,4-dimethyl-2-(4'-benzyloxycarbonylbiphenyl-2yl)oxazoline

(6)4,4-dimethyl-2-(4'-tetrahydropyranyloxycarbonylbiphenyl-2-yl)oxazoline

Further, the methyl-biphenyloxazoline derivative (IX) according to thepresent invention has the following chemical structural formula:##STR53##

Further, specific and representative examples of themethyl-biphenyloxazoline derivative (IX) according to the presentinvention include the following compounds, though the derivative (IX) isnot limited to them.

(1) 4,4-dimethyl-2-(4'-methyl-biphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-(4'-methyl-biphenyl-3-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-methyl-biphenyl-4-yl)oxazoline

Next, each step of the process according to the present invention willbe described in detail hereinafter (see the above reaction scheme-7).

Step 1

This step is one wherein 4-bromobenzyl alcohol is protected to obtain a4-bromobenzyl ether derivative (VI). This step can be conductedaccording to the conventional process for introducing a protective groupfor a hydroxyl group in organic synthesis. Specific examples of thereagent for introducing a protective group usable in the presentinvention include chloro-methyl methyl ether, 2-chloroethyl methylether, chloromethyl phenyl ether, chloromethy benzyl ether, chloromethylmethoxyethyl ether, chloromethyl methyl sulfide, dihydropyrane,dihydrofuran, chlorotrimethylsilane, chlorotriethylsilane,chlorotriphenylsilane, methyl iodide, benzyl chloride andchlorotriphenylmethane.

Step 2

This step is one wherein the 4-bromobenzyl ether derivative (VI) iscoupled with oxazolylanisole to form an alkoxymethyl-biphenyloxazolinederivative (V) through the Grignard reaction. This reaction can beconducted by the conventional process for the Grignard reaction asdescribed in, e.g., Journal of Organic Chemistry (J. Org. Chem.), 43(7), 1372 to 1379, 1978.

Step 3

In this step, the protective group of the alkoxymethyl-biphenyloxazolinederivative (V) is eliminated to form a hydroxymethyl-biphenyloxazolinederivative (IV). This reaction can be conducted according to a commonprocess for eliminating the protective group such as hydrolysis andcatalytic reduction.

Step 4

Step 4 is one wherein a methyl-biphenyloxazoline derivative (IX) isoxidized into a carboxy-biphenyloxazoline derivative (VII). In thisreaction, an oxidizing agent is used, and specific examples thereofusable in the present invention include permanganates, chromium oxideand bichromates, among which permanganates are preferable. This reactioncan be conducted according to the process described in, e.g., OrganicSynthesis, Col. Vol. II, 135. In the present invention, themethyl-biphenyloxazoline derivative (IX) is dissolved in a solvent, apermanganate such as potassium permanganate is added thereto, and theobtained mixture is heated.

Although the amount of the permanganate used is not limited, it isgenerally used in an amount of about 1 to 100 equivalents, morepreferably about 2 to 50 equivalents, still preferably about 3 to 20equivalents per equivalent of the methyl-biphenyloxazoline derivative(IX).

The solvent to be used in this reaction is not limited, so far as it isinert to the methyl-biphenyloxazoline derivative (IX) or the oxidizingagent. Specific examples thereof include water, pyridine, formic acidand acetic acid. The solvent may be used either alone or as a mixture oftwo or more of them. Although the amount of the solvent used is notlimited, it is generally used in an amount of about 0.5 to 100 parts byvolume, more preferably about 0.5 to 50 parts by volume, stillpreferably about 1 to 20 parts by volume based on 1 part by weight ofthe methyl-biphenyloxazoline derivative (IX).

This reaction is generally conducted under heating at a temperatureranging from 50° C. to the refluxing temperature of the solvent.Although the reaction time varies depending upon the kind or amount ofthe oxidizing agent, temperature or the like, it is generally completedin about 1 to 48 hours.

Steps 5 and 7

These steps are those wherein the carboxybiphenyloxazoline derivative(VII) or the alkoxycarbonyl-biphenyloxazoline derivative (VIII) isreduced with a metal hydride complex into ahydroxymethyl-biphenyloxazoline derivative (IV). Specific examples ofthe metal hydride complex in the present invention include aluminumlithium hydride, bis(2-methoxyethoxy)aluminum sodium hydride,diisobutylaluminum hydride and diborane. Although the amount of themetal hydride complex used is not limited, it is generally used in anamount of about 0.2 to 50 equivalents, more preferably about 0.5 to 20equivalents, still preferably about 1 to 10 equivalents per equivalentof the carboxy-biphenyloxazoline derivative (VII) or thealkoxycarbonylbiphenyloxazoline derivative (VIII).

It is preferable to use a solvent in this reaction. The solvent usableis not limited, so far as it is inert to the carboxy-biphenyloxazolinederivative (VII) or the alkoxycarbonyl-biphenyloxazoline derivative(VIII), or the metal hydride complex. Specific examples thereof includetetrahydrofuran, 1,2-dimethoxyethane, ethyl ether, isopropyl ether,2-methoxyethyl ether, dioxane, dioxolane, benzene, toluene, hexane andoctane. The solvent may be used either alone or as a mixture of two ormore of them. Although the amount thereof used is not limited, it isgenerally used in an amount of about 0.5 to 100 parts by volume, morepreferably about 0.5 to 50 parts by volume, still preferably about 1 to20 parts by volume based on 1 part by weight of thecarboxy-biphenyloxazoline derivative (VII) or thealkoxycarbonyl-biphenyloxazoline derivative (VIII).

Although this reaction can be generally conducted at a temperatureranging from -70° C. to the refluxing temperature of the solvent, it isgenerally conducted under cooling with ice. Although the reaction timevaries depending upon the kind or amount of the metal hydride complex,temperature or the like, it is generally completed in about 5 minutes to6 hours.

Step 6

This step is one wherein the carboxy-biphenyloxazoline derivative (VII)obtained in step 4 is esterified into analkoxycarbonyl-biphenyloxazoline derivative (VIII). This reaction can beconducted according to the common esterification process.

Step 8

This step is one wherein the protective group of thehydroxymethyl-biphenyloxazoline derivative (IV) is eliminated to form ahydroxymethyl-biphenylcarboxylic acid derivative (III). Although thisreaction can be conducted by the conventional processes for hydrolyzingoxazoline into a carboxylic acid in organic synthesis, i.e., by acidichydrolysis, basic hydrolysis, a process using methyl iodide and sodiumhydroxide described in Journal of Organic Chemistry (J. Org. Chem.),39(3), 2778, 1974, or a combination thereof, sulfuric acid hydrolysis, acombination of hydrochloric acid hydrolysis and sodium hydroxidehydrolysis, or the above process using methyl iodide and sodiumhydroxide is preferable in the present invention.

Step 9

This step is one wherein the hydroxymethyl-biphenylcarboxylic acidderivative (III) is esterified into a hydroxymethyl-biphenylcarboxylicester derivative (II). This reaction can be conducted according to thecommon esterification process.

Step 10

This step is one wherein a sulfonyloxybiphenylcarboxylic esterderivative (I) is prepared through the sulfonylation of thehydroxymethyl-biphenylcarboxylic ester derivative (II).

In the present invention, the sulfonylation is conducted according tothe conventional process with a reagent for sulfonylation such asmethanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonylchloride and p-toluenesulfonyl chloride. Although the amount of thereagent for sulfonylation used is not limited, it is generally used inan amount of about 1 to 50 equivalents, more preferably about 1.2 to 20equivalents, still preferably 1.5 to 10 equivalents per equivalent ofthe hydroxymethyl-biphenyloxazoline derivative (II).

The sulfonyloxy-biphenylcarboxylic ester derivative (I) according to thepresent invention is highly stable and can be further purified by anordinary method such as silica gel column chromatography and vacuumdistillation.

Then, a hydroxymethyl-biphenylcarboxylic acid derivative (X) representedby the following general formula is a novel compound and is useful as anintermediate for the preparation of the sulfonyloxybiphenylcarboxylicester derivative (I) according to the present invention: ##STR54##

In the formula, R⁵ represents a hydrogen atom, a lower alkyl group, anaryl group, an aralkyl group, a cycloether group, a trialkylsilyl group,a triarylsilyl group, a vinyl group, a lower alkoxyalkyl group, anaryloxyalkyl group, an aralkyloxyalkyl group, a thioalkoxyalkyl group ora triphenylmethyl group.

Further specific examples of the lower alkyl group include groups having1 to 6 carbon atoms, such as a methyl group, an ethyl group, a n-propylgroup, an i-propyl group, a n-butyl group, an i-butyl group, a t-butylgroup, a pentyl group and a hexyl group; those of the aryl group includea phenyl group, a tolyl group and a xylyl group; those of the aralkylgroup include a benzyl group and a phenethyl group; those of thecycloether group include a tetrahydropyranyl group and atetrahydrofuranyl group; those of the trialkylsilyl group include atrimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilylgroup, an i-propyldimethylsilyl group and a phenyldimethylsilyl group;that of the triarylsilyl group includes a triphenylsilyl group; those ofthe lower alkoxyalkyl group include a methoxymethyl group, anethoxymethyl group, a propoxymethyl group, a methoxyethyl group, anethoxyethyl group, a propoxyethyl group and a propoxypropyl group; thoseof the aryloxyalkyl group include a phenoxymethyl group, a phenoxyethylgroup and a tolyloxymethyl group; those of the aralkyloxyalkyl groupinclude a benzyloxymethyl group and a phenethyloxymethyl group; andthose of the thioalkoxyalkyl group include a methylthiomethyl group, amethylthioethyl group, an ethylthiomethyl group, a phenylthiomethylgroup and a benzylthiomethyl group.

Further specific and representative examples of thehydroxymethyl-biphenylcarboxylic acid derivative (X) include thefollowing compounds, though the hydroxymethyl-biphenylcarboxylic acidderivative (X) according to the present invention is not limited tothem.

(1) 2-(4'-hydroxymethylphenyl)benzoic acid

(2) 3-(4'-hydroxymethylphenyl)benzolc acid

(3) 4-(4'-hydroxymethylphenyl)benzolc acid

(4) methyl 2-(4'-hydroxymethylphenyl)benzoate

(5) ethyl 2-(4'-hydroxymethylphenyl)benzoate

(6) propyl 2-(4'-hydroxymethylphenyl)benzoate

(7) t-butyl 2-(4'-hydroxymethylphenyl)benzoate

(8) phenyl 2-(4'-hydroxymethylphenyl)benzoate

(9) benzyl 2-(4'-hydroxymethylphenyl)benzoate

(10) tetrahydropyranyl 2-(4'-hydroxymethylphenyl)benzoate

(11) tetrahydrofuranyl 2-(4'-hydroxymethylphenyl)benzoate

(12) trimethylsilyl 2-(4'-hydroxymethylphenyl)benzoate

(13) methoxymethyl 2-(4'-hydroxymethylphenyl)benzoate

(14) thiomethoxymethyl 2-(4'-hydroxymethylphenyl)benzoate

Then, the present inventors have extensively studied to develop a novelprocess for the preparation of a halomethyl-biphenylcarboxylic esterderivative (II) improved in the above disadvantages. As a result, theyhave found that the object can be attained by any of the followingprocesses, and have accomplished the present invention.

(1) halogenating a hydroxymethyl-biphenylcarboxylic ester derivative(I).

(2) esterifying a hydroxymethyl-biphenylcarboxylic acid derivative (III)into a hydroxymethyl-biphenylcarboxylic ester derivative (I) and furtherhalogenating it.

(3) eliminating the protective group of ahydroxymethyl-biphenyloxazoline derivative (IV) to form ahydroxymethyl-biphenylcarboxylic acid derivative (III), then esterifyingit into a hydroxymethyl-biphenylcarboxylic ester derivative (I), andfurther halogenating it.

(4) eliminating the protective group of analkoxymethyl-biphenyloxazoline derivative (V) to form ahydroxymethyl-biphenyloxazoline derivative (IV), eliminating theprotective group thereof to form a hydroxymethyl-biphenylcarboxylic acidderivative (III), then esterifying it into ahydroxymethyl-biphenylcarboxylic ester derivative (I), and furtherhalogenating it.

(5) coupling a 4-bromobenzyl ether derivative (VI) with oxazolylanisoleto form an alkoxymethyl-biphenyloxazoline derivative (V) through theGrignard reaction, eliminating the protective group thereof to form ahydroxymethyl-biphenyloxazoline derivative (IV), eliminating theprotective group thereof to form a hydroxymethyl-biphenylcarboxylic acidderivative (III), then esterifying it into ahydroxymethyl-biphenylcarboxylic ester derivative (I), and furtherhalogenating it.

(6) protecting 4-bromobenzyl alcohol to form a 4-bromobenzyl etherderivative (VI), coupling it with oxazolylanisole to form analkoxymethyl-biphenyloxazoline derivative (V) through the Grignardreaction, eliminating the protective group thereof to form ahydroxymethyl-biphenyloxazoline derivative (IV), eliminating theprotective group thereof to form a hydroxymethyl-biphenylcarboxylic acidderivative (III), then esterifying it into ahydroxymethyl-biphenylcarboxylic ester derivative (I), and furtherhalogenating it.

(7) reducing a carboxy-biphenyloxazoline derivative (VII) or analkoxycarbonyl-biphenyloxazoline derivative (VIII) with a metal hydridecomplex into a hydroxymethyl-biphenyloxazoline derivative (IV),eliminating the protective group thereof to form ahydroxymethyl-biphenylcarboxylic acid derivative (III), then esterifyingit into a hydroxymethyl-biphenylcarboxylic ester derivative (I), andfurther halogenating it.

(8) esterifying a carboxy-biphenyloxazoline derivative (VII) with alower alcohol to form an alkoxycarbonyl-biphenyloxazoline derivative(VIII), reducing it with a metal hydride complex into ahydroxymethyl-biphenyloxazoline derivative (IV), eliminating theprotective group thereof to form a hydroxymethyl-biphenylcarboxylic acidderivative (III), then esterifying it into ahydroxymethyl-biphenylcarboxylic ester derivative (I), and furtherhalogenating it.

(9) oxidizing a methyl-biphenyloxazoline derivative (IX) with anoxidizing agent into a carboxy-biphenyloxazoline derivative (VII),either esterifying it with a lower alcohol to form analkoxycarbonyl-biphenyloxazoline derivative (VIII) and reducing it witha metal hydride complex or reducing it with a metal hydride complexdirectly to form a hydroxymethyl-biphenyloxazoline derivative (IV),eliminating the protective group thereof to form ahydroxymethyl-biphenylcarboxylic acid derivative (III), then esterifyingit into a hydroxymethyl-biphenylcarboxylic ester derivative (I), andfurther halogenating it.

The outline of the reaction path according to the present invention isrepresented by the following chemical reaction formula (reactionscheme-8). ##STR55##

Accordingly, an object of the present invention is to provide a processfor the preparation of a halo-methyl-biphenylcarboxylic ester derivative(II) which is an active intermediate useful for the introduction of theside chain of biphenyl in preparing a2-alkyl-3-(2'-alkoxycarbonylbiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative which is an antagonist against angiotensin II receptor usefulas an antihypertensive drug and a remedy for hemal lesions.

The hydroxymethyl-biphenylcarboxylic ester derivative (I) according tothe present invention has the following general formula: ##STR56##

In the formula, R¹ represents a lower alkyl group, an aryl group, anaralkyl group, a cycloether group, a triarylsilyl group, a vinylgroup,.a lower alkoxyalkyl group, an aryloxyalkyl group, anaralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethylgroup. Specific examples of the lower alkyl group include groups having1 to 6 carbon atoms, such as a methyl group, an ethyl group, a n-propylgroup, an i-propyl group, a n-butyl group, an i-butyl group, a t-butylgroup, a pentyl group and a hexyl group; those of the aryl group includea phenyl group, a tolyl group and a xylyl group; those of the aralkylgroup include a benzyl group and a phenethyl group; those of thecycloether group include a tetrahydropyranyl group and atetrahydrofuranyl group; those of the triarylsilyl group include atrimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilylgroup, an i-propyldimethylsilyl group and a phenyldimethylsilyl group;those of the lower alkoxyalkyl group include a methoxymethyl group, anethoxymethyl group, a propoxymethyl group, a methoxyethyl group, anethoxyethyl group, a propoxyethyl group and a propoxypropyl group; thoseof the aryloxyalkyl group include a phenoxymethyl group, a phenoxyethylgroup and a tolyloxymethyl group; those of the aralkyloxyalkyl groupinclude a benzyloxymethyl group and a phenethyloxymethyl group; andthose of the thioalkoxyalkyl group include a methylthiomethyl group, amethylthioethyl group, an ethylthiomethyl group, a phenylthiomethylgroup and a benzylthiomethyl group.

Specific examples of the hydroxymethyl-biphenylcarboxylic esterderivative (I) include the following compounds, though thehydroxymethyl-biphenylcarboxylic ester derivative (I) according to thepresent invention is not limited to them.

methyl 2-(4'-hydroxymethylphenyl)benzoate

(2) methyl 3-(4'-hydroxymethylphenyl)benzoate

(3) methyl 4-(4'-hydroxymethylphenyl)benzoate

(4) ethyl 2-(4'-hydroxymethylphenyl)benzoate

(5) ethyl 3-(4'-hydroxymethylphenyl)benzoate

(6) ethyl 4-(4'-hydroxymethylphenyl)benzoate

Then, the halomethyl-biphenylcarboxylic ester derivative (II) accordingto the present invention has the following general formula: ##STR57##

In the formula, R¹ and X are each as defined above. Further specificexamples of the halomethyl-biphenylcarboxylic ester derivative (II)according to the present invention include the following compounds,though the derivative (II) is not limited to them.

(1) methyl 2-(4'-bromomethylphenyl)benzoate

(2) methyl 2-(4'-chloromethylphenyl)benzoate

(3) methyl 2-(4'-iodomethylphenyl)benzoate

(4) methyl 2-(4'-fluoromethylphenyl)benzoate

(5) methyl 3-(4'-bromomethylphenyl)benzoate

(6) methyl 3-(4'-chloromethylphenyl)benzoate

(7) methyl 4-(4'-bromomethylphenyl)benzoate

(8) methyl 4-(4'-chloromethylphenyl)benzoate

(9) ethyl 2-(4'-bromomethylphenyl)benzoate

(10) ethyl 2-(4'-chloromethylphenyl)benzoate

(11) ethyl 3-(4'-bromomethylphenyl)benzoate

(12) ethyl 3-(4'-chloromethylphenyl)benzoate

(13) ethyl 4-(4'-bromomethylphenyl)benzoate

(14) ethyl 4-(4'-chloromethylphenyl)benzoate

Then, the hydroxymethyl-biphenylcarboxylic acid derivative (III) has thefollowing chemical structural formula: ##STR58##

Further specific examples of the hydroxymethyl-biphenylcarboxylic acidderivative (III) include the following compounds, though thehydroxymethyl-biphenylcarboxylic acid derivative (III) according to thepresent invention is not limited to them.

(1) 2-(4'-hydroxymethyl)benzoic acid

(2) 3-(4'-hydroxymethyl)benzoic acid

(3) 4-(4'-hydroxymethyl)benzoic acid

Further, the hydroxymethyl-biphenyloxazoline derivative (IV) accordingto the present invention has the following chemical structural formula:##STR59##

Further specific examples of the hydroxymethyl-biphenyloxazolinederivative (IV) according to the present invention include the followingcompounds, though the derivative (IV) is not limited to them.

(1) 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-('4'-hydroxymethyl-biphenyl-3-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-4-yl)oxazoline

Then, the alkoxymethyl-biphenyloxazoline derivative (V) has thefollowing chemical structural formula: ##STR60##

In the formula, R² represents a lower alkoxyalkyl group, an aryloxyalkylgroup, an aralkyloxyalkyl group, a lower alkoxyalkoxyalkyl group, athioalkoxyalkyl group, a cycloether group, a trialkylsilyl group, atriarylsilyl group, a lower alkyl group, a vinyl group, an aralkyl groupor a triphenylmethyl group.

Further specific examples of the lower alkoxyalkyl group include amethoxymethyl group, an ethoxymethyl group, a propoxymethyl group, amethoxyethyl group, an ethoxyethyl group, a propoxyethyl group and apropoxypropyl group; those of the aryloxyalkyl group include aphenoxymethyl group, a phenoxyethyl group and a tolyloxymethyl group;those of the aralkyloxyalkyl group include a benzyloxymethyl group and aphenethyloxymethyl group; those of the lower alkoxyalkoxyalkyl groupinclude a methoxyethoxymethyl group and an ethoxyethoxymethyl group;those of the thioalkoxyalkyl group include a methylthiomethyl group, amethylthioethyl group, an ethylthiomethyl group, a phenylthiomethylgroup and a benzylthiomethyl group; those of the cycloether groupinclude a tetrahydropyranyl group and a tetrahydrofuranyl group; thoseof the trialkylsilyl group include a trimethylsilyl group, atriethylsilyl group, a t-butyldimethylsilyl group, ani-propyldimethylsilyl group and a phenyldimethylsilyl group; that of thetriarylsilyl group include a triphenylsilyl group; those of the loweralkyl group include a methyl group, an ethyl group, a propyl group and at-butyl group; and those of the aralkyl group include a benzyl group, aphenethyl group, a methylbenzyl group, a trimethylbenzyl group, anitrobenzyl group and a phenacyl group.

Further, specific and representative examples of thealkoxymethyl-biphenyloxazoline derivative (V) include the followingcompounds, though the alkoxymethyl-biphenyloxazoline derivative (V)according to the present invention is not limited to them.

(1) 4,4-dimethyl-2-(4'-methoxymethoxymethyl-biphenyl-2-yl)oxazoline

(2)4,4-dimethyl-2-(4'-methoxyethoxymethoxymethyl-biphenyl-2-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-thiomethoxymethoxymethyl-biphenyl-2-yl)oxazoline

(4)4,4-dimethyl-2-(4'-tetrahydropyranyloxymethyl-biphenyl-2-yl)oxazoline

(5)4,4-dimethyl-2-(4'-tetrahydrofuranyloxymethyl-biphenyl-2-yl)oxazoline

(6) 4,4-dimethyl-2-(4'-trimethylsilyloxymethyl-biphenyl-2-yl)oxazoline

(7) 4,4-dimethyl-2-(4'-t-butoxymethyl-biphenyl-2yl)oxazoline

(8) 4,4-dimethyl-2-(4'-benzyloxymethyl-biphenyl-2yl)oxazoline

Further, the 4-bromobenzyl ether derivative (VI) according to thepresent invention has the following chemical structural formula:##STR61##

In the formula, R² is as defined above. Further specific examples of the4-bromobenzyl ether derivative (VI) include the following compounds,though the 4-bromobenzyl ether derivative (VI) according to the presentinvention is not limited to them.

(1) 4-bromobenzyl-methoxymethyl ether

(2) 4-bromobenzyl-methoxyethoxymethyl ether

(3) 4-bromobenzyl-thiomethoxymethyl ether

(4) 4-bromobenzyl-tetrahydropyranyl ether

(5) 4-bromobenzyl-tetrahydrofuranyl ether

(6) 4-bromobenzyl-trimethylsilyl ether

(7) 4-bromobenzyl-t-butyl ether

(8) 4-bromobenzyl-benzyl ether

Further, the carboxy-biphenyloxazoline derivative (VII) according to thepresent invention has the following chemical structural formula:##STR62##

Further specific examples of the carboxybiphenyloxazoline derivative(VII) according to the present invention include the followingcompounds, though the derivative (VII) is not limited to them.

(1) 4,4-dimethyl-2-(4'-carboxybiphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-(4'-carboxybiphenyl-3-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-carboxybiphenyl-4-yl)oxazoline

Further, the alkoxycarbonyl-biphenyloxazoline derivative (VIII)according to the present invention has the following chemical structuralformula: ##STR63##

In the formula, R³ represents a lower alkyl group, an aryl group, anaralkyl group, a cycloether group, a trialkylsilyl group, a triarylsilylgroup, a vinyl group, a lower alkoxyalkyl group, an aryloxyalkyl group,an aralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethylgroup. It is preferable that R³ be a lower alkyl group, an aryl group,an aralkyl group, a cycloether group, a triarylsilyl group, a vinylgroup, a lower alkoxyalkyl group, an aryloxyalkyl group, anaralkyloxyalkyl group, a thioalkoxyalkyl group or a triphenylmethylgroup. Specific examples of the lower alkyl group include groups having1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propylgroup, a butyl group, a pentyl group and a hexyl group; those of thearyl group include a phenyl group, a tolyl group and a xylyl group;those of the aralkyl group include a benzyl group and a phenethyl group;those of the cycloether group include a tetrahydropyranyl group and atetrahydrofuranyl group; those of the triarylsilyl group include atrimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilylgroup, an i-propyldimethylsilyl group and a phenyldimethylsilyl group;those of the lower alkoxyalkyl group include a methoxymethyl group, anethoxymethyl group, a propoxymethyl group, a methoxyethyl group, anethoxyethyl group, a propoxyethyl group and a propoxypropyl group; thoseof the aryloxyalkyl group include a phenoxymethyl group, a phenoxyethylgroup and a tolyloxymethyl group; those of the aralkyloxyalkyl groupinclude a benzyloxymethyl group and a phenethyloxymethyl group; andthose of the thioalkoxyalkyl group include a methylthiomethyl group, amethylthioethyl group, an ethylthiomethyl group, a phenylthiomethylgroup and a benzylthiomethyl group.

Further specific examples of the alkoxycarbonylbiphenyloxazolinederivative (VIII) include the following compounds, though thealkoxycarbonylbiphenyloxazoline derivative (VIII) according to thepresent invention is not limited to them.

(1) 4,4-dimethyl-2-(4'-methoxycarbonylbiphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-(4'-ethoxycarbonylbiphenyl-2-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-propoxycarbonylbiphenyl-2-yl)oxazoline

(4) 4,4-dimethyl-2-(4'-phenoxycarbonylbiphenyl-2-yl)oxazoline

(5) 4,4-dimethyl-2-(4'-benzyloxycarbonylbiphenyl-2yl)oxazoline

(6)4,4-dimethyl-2-(4'-tetrahydropyranyloxycarbonylbiphenyl-2-yl)oxazoline

Further, the methyl-biphenyloxazoline derivative (IX) according to thepresent invention has the following chemical structural formula:##STR64##

Further, specific and representative examples of themethyl-biphenyloxazoline derivative (IX) according to the presentinvention include the following compounds, though the derivative (IX) isnot limited to them.

(1) 4,4-dimethyl-2-(4'-methyl-biphenyl-2-yl)oxazoline

(2) 4,4-dimethyl-2-(4'-methyl-biphenyl-3-yl)oxazoline

(3) 4,4-dimethyl-2-(4'-methyl-biphenyl-4-yl)oxazoline

Next, each step of the process according to the present invention willbe described in detail hereinafter (see the above reaction scheme-8).

Step 1

This step is one wherein 4-bromobenzyl alcohol is protected to obtain a4-bromobenzyl ether derivative (VI). This step can be conductedaccording to the conventional process for introducing a protective groupfor a hydroxyl group in organic synthesis. Specific examples of thereagent for introducing a protective group usable in the presentinvention include chloromethyl methyl ether, 2-chloroethyl methyl ether,chloromethyl phenyl ether, chloromethyl benzyl ether, chloromethylmethoxyethyl ether, chloromethyl methyl sulfide, dihydropyrane,dihydrofuran, chlorotrimethylsilane, chlorotriethylsilane,chlorotriphenylsilane, methyl iodide, benzyl chloride andchlorotriphenylmethane.

Step 2

This step is one wherein the 4-bromobenzyl ether derivative (VI) iscoupled with oxazolylanisole to form an alkoxymethyl-biphenyloxazolinederivative (V) through the Grignard reaction. This reaction can beconducted according to the conventional process for the Grignardreaction as described in, e.g., Journal of Organic Chemistry (J. Org.Chem.), 43 (7), 1372 to 1379, 1978.

Step 3

In this step, the protective group of the alkoxymethyl-biphenyloxazolinederivative (V) is eliminated to form a hydroxymethyl-biphenyloxazolinederivative (IV). This reaction can be conducted according to a commonprocess for eliminating the protective group such as hydrolysis andcatalytic reduction. This reaction can be conducted according to acommon process for eliminating the protective group such as hydrolysisand catalytic reduction.

Step 4

Step 4 is one wherein a methyl-biphenyloxazoline derivative (IX) isoxidized into a carboxy-biphenyloxazoline derivative (VII). In thisreaction, an oxidizing agent is used, and specific examples thereofusable in the present invention include permanganates, chromium oxideand bichromates, among which permanganates are preferable. This reactioncan be conducted according to the process described in, e.g., OrganicSynthesis, Col. Vol. II, 135. In the present invention, themethyl-biphenyloxazoline derivative (IX) is dissolved in a solvent, apermanganate such as potassium permanganate is added thereto, and theobtained mixture is heated.

Although the amount of the permanganate used is not limited, it isgenerally used in an amount of about 1 to 100 equivalents, morepreferably about 2 to 50 equivalents, still preferably about 3 to 20equivalents per equivalent of the methyl-biphenyloxazoline derivative(IX).

The solvent to be used in this reaction is not limited, so far as it isinert to the methyl-biphenyloxazoline derivative (IX) or the oxidizingagent. Specific examples thereof include water, pyridine, formic acidand acetic acid. The solvent may be used either alone or as a mixture oftwo or more of them. Although the amount of the solvent used is notlimited, it is generally used in an amount of about 0.5 to 100 parts byvolume, more preferably about 0.5 to 50 parts by volume, stillpreferably about 1.0 to 20 parts by volume based on 1 part by weight ofthe methyl-biphenyloxazoline derivative (IX).

This reaction is generally conducted under heating at a temperatureranging from 50° C. to the refluxing temperature of the solvent.Although the reaction time varies depending upon the kind or amount ofthe oxidizing agent, temperature or the like, it is generally completedin about 1 to 48 hours.

Steps 5 and 7

These steps are those wherein the carboxybiphenyloxazoline derivative(VII) or the alkoxycarbonyl-biphenyloxazoline derivative (VIII) isreduced with a metal hydride complex into ahydroxymethyl-biphenyloxazoline derivative (IV). Specific examples ofthe metal hydride complex in the present invention include aluminumlithium hydride, bis(2-methoxyethoxy)aluminum sodium hydride,diisobutylaluminum hydride and diborane. Although the amount of themetal hydride complex used is not limited, it is generally used in anamount of about 0.2 to 50 equivalents, more preferably about 0.5 to 20equivalents, still preferably about 1 to 10 equivalents per equivalentof the carboxy-biphenyloxazoline derivative (VII) or thealkoxycarbonylbiphenyloxazoline derivative (VIII).

It is preferable to use a solvent in this reaction. The solvent usableis not limited, so far as it is inert to the carboxy-biphenyloxazolinederivative (VII) or the alkoxycarbonyl-biphenyloxazoline derivative(VIII), or the metal hydride complex. Specific examples thereof includetetrahydrofuran, 1,2-dimethoxyethane, ethyl ether, isopropyl ether,2-methoxyethyl ether, dioxane, dioxolane, benzene, toluene, hexane andoctane. The solvent may be used either alone or as a mixture of two ormore of them. Although the amount of the solvent used is not limited, itis generally used in an amount of about 0.5 to 100 parts by volume, morepreferably about 0.5 to 50 parts by volume, still preferably about 1.0to 20 parts by volume based on 1 part by weight of thecarboxy-biphenyloxazoline derivative (VII) or thealkoxycarbonyl-biphenyloxazoline derivative (VIII).

Although this reaction can be generally conducted at a temperatureranging from -70° C. to the refluxing temperature of the solvent, it isgenerally conducted under cooling with ice. Although the reaction timevaries depending upon the kind or amount of the metal hydride complex,temperature or the like, it is generally completed in about 5 minutes to6 hours.

Step 6

This step is one wherein the carboxy-biphenyloxazoline derivative (VII)obtained in step 4 is esterified into analkoxycarbonyl-biphenyloxazoline derivative (VIII). This reaction can beconducted according to the common esterification process.

Step 8

This step is one wherein the protective group of thehydroxymethyl-biphenyloxazoline derivative (IV) is eliminated to form ahydroxymethyl-biphenylcarboxylic acid derivative (III). Although thisreaction can be conducted by the conventional processes for hydrolyzingoxazoline into a carboxylic acid in organic synthesis, i.e., by acidichydrolysis, basic hydrolysis, a process using methyl iodide and sodiumhydroxide described in Journal of Organic Chemistry (J. Org. Chem.),39(3), 2778, 1974, or a combination thereof, sulfuric acid hydrolysis, acombination of hydrochloric acid hydrolysis and sodium hydroxidehydrolysis, or the above process using methyl iodide and sodiumhydroxide is preferable in the present invention.

Step 9

This step is one wherein the hydroxymethyl-biphenylcarboxylic acidderivative (III) is esterified into a hydroxymethyl-biphenylcarboxylicester derivative (I). This reaction can be conducted according to thecommon esterification process.

Step 10

This step is one wherein the hydroxymethyl-biphenylcarboxylic esterderivative (I) is halogenated into a halomethyl-biphenylcarboxylic esterderivative (II). This reaction is conducted according to theconventional manner by the use of a reagent for halogenation such ashydrochloric acid, thionyl chloride, sulfuryl chloride, phosphorustrichloride, phosphorus pentachloride, phosphorus oxychloride, oxalylchloride, phosgene, diphosgene, triphosgene, hydrobromic acid, thionylbromide and phosphorus tribromide. Although the amount of the reagentfor halogenation used is not limited, it is generally used in an amountof about 1 to 50 equivalents, preferably about 1.5 to 20 equivalents,still preferably about 2 to 10 equivalents per equivalent of thehydroxymethyl-biphenylcarboxylic ester derivative (I).

The halomethyl-biphenylcarboxylic ester derivative (II) according to thepresent invention is highly stable and can also be further purified byan ordinary method such as silica gel column chromatography and vacuumdistillation.

Further, a (4'-chloromethylphenyl)benzoic ester (X) represented by thefollowing general formula is a novel compound and is useful as anintermediate for the synthesis of a medicine: ##STR65## [wherein R¹ isas defined above].

Specific examples of the (4'-chloromethylphenyl)benzoic ester (X)include the following compounds, though the(4'-chloromethylphenyl)benzoic ester (X) according to the presentinvention is not limited to them.

(1) methyl 2-(4'-chloromethyl)benzoate

(2) methyl 3-(4'-chloromethyl)benzoate

(3) methyl 4-(4'-chloromethyl)benzoate

(4) ethyl 2-(4'-chloromethyl)benzoate

(5) ethyl 3-(4'-chloromethyl)benzoate

(6) ethyl 4-(4'-chloromethyl)benzoate

(7) propyl 2-(4'-chloromethyl)benzoate

(8) propyl 3-(4'-chloromethyl)benzoate

(9) propyl 4-(4'-chloromethyl)benzoate

(10) phenyl 2-(4'-chloromethyl)benzoate

(11) phenyl 3-(4'-chloromethyl)benzoate

(12) phenyl 4-(4'-chloromethyl)benzoate

Preparative Examples for the raw materials and intermediates necessaryfor carrying out the present invention with now be described prior toExamples.

Preparative Example 1

Synthesis of 4-bromobenzylmethoxymethyl ether ##STR66##

10.0 g (53.5 mmol) of 4-bromobenzyl alcohol was dissolved intetrahydrofuran (200 ml). 6.6 g (58.8 mmol) of potassium t-butoxide wasadded thereto under cooling with ice, followed by stirring for one hour.Then, 5.2 g (64.6 mmol) of chloromethyl methyl ether was dropwise addedthereto, followed by stirring at room temperature for 12 hours. Thereaction liquid was added to a saturated aqueous solution of ammoniumchloride, followed by the extraction with ethyl acetate. After washingwith water and drying, vacuum concentration was conducted. The residuewas purified by silica gel column chromatography to give 11.0 g of thetitle compound as an oil (yield 89%).

1H-NMR(90 MHz, CDCl₃); δ (ppm) 3.40(3H, s), 4.52(2H, s), 4.66(2H, s),7.16(2H, d, J=8.0Hz), 7.40(2H, d, J=8.0Hz)

Preparative Example 2

Synthesis of 4-bromobenzyltetrahydropylanyl ether ##STR67##

10.0 g (53.5 mmol) of 4-bromobenzyl alcohol and 4.95 g (58.8 mmol) of3,4-dihydro-2H-pyrane were dissolved in methylene chloride (50 ml).Under cooling with ice, 100 mg of p-toluenesulfonic acid monohydrate wasadded thereto, followed by stirring for 3 hours. The reaction liquid wasadded to an aqueous solution of sodium hydrogencarbonate, followed bythe extraction with chloroform. After washing with water and drying,vacuum concentration was conducted. The residue was subjected to vacuumdistillation (160° C./1 mmHg) to give 12.0 g of the title compound as anoil (yield 83%).

¹ H-NMR(90MHz, CDCl₃); δ (ppm) 1.40˜2.10 (6H, m), 3.38˜3.70 (1H, m),3.70˜4.02 (1H, m), 4.41 (1H, d, J=13.0 Hz), 4.64(1H, s), 4.70(1H, d,J=13.0 Hz), 7.18(2H, d, J=8.0 Hz), 7.44 (2H, d, J=8.0 Hz)

Preparative Example 3

Synthesis of 4,4-dimethyl-2-(4'-methyl-biphenyl-2-yl) oxazoline##STR68##

Tetrahydrofuran (200 ml) was added to 2.5 g (103 mmol) of flakymagnesium, followed by the addition of a small amount of dibromoethaneunder stirring. After the confirmation of bubbling, 13 ml (106 mmol) of4-bromotoluene was dropwise added thereto. After the confirmation of thedissolution of the magnesium, the mixture was further stirred at roomtemperature for one hour. This reaction liquid was dropwise added to asolution of 10.0 g (48.7 mmol) of4,4-dimethyl-2-(2'-methoxyphenyl)oxazoline in tetrahydrofuran (100 ml),followed by stirring for 12 hours. The reaction liquid was poured into asaturated aqueous solution of ammonium chloride, followed by theextraction with chloroform. After washing with water and drying, vacuumconcentration was conducted. The residue was purified by silica gelcolumn chromatography (a n-hexane/ethyl acetate system) to give 11.0 gof the title compound as a crystal (yield 85%).

m.p.; 56°-59° C.

¹ H-NMR(200 MHz, CDCl₃); δ (ppm) 1.30 (6H, s), 2.38(3H, s), 3.80(2H, s),7.00˜7.50(7H, m), 7.70(1H, dd, J=7.5, 1.5 Hz)

FAB-MS; 266(MH⁺)

Next, Examples will be given hereinafter to illustrate the presentinvention in definite, though it is needless to say that the presentinvention is not limited to them.

EXAMPLE 1 Synthesis of4,4-dimethyl-2-(4'-methoxymethoxymethyl-biphenyl-2-yl)oxazoline##STR69##

Tetrahydrofuran (15 ml) was added to 408 mg (16.8 mmol) of flakymagnesium, followed by the addition of a small amount of dibromoethaneunder stirring. After the confirmation of bubbling, a solution of 3.23 g(14.0 mmol) of 4-bromobenzyl-methoxymethyl ether in tetrahydrofuran (15ml) was dropwise added thereto. After the confirmation of thedissolution of the magnesium, the resulting mixture was further stirredat room temperature for one hour. Then, a solution of 2.10 g (10.2 mmol)of 4,4-dimethyl-2-(2'-methoxyphenyl)oxazoline in tetrahydrofuran (15 ml)was dropwise added thereto, followed by stirring for 12 hours. Thereaction liquid was poured into a saturated aqueous solution of ammoniumchloride, followed by the extraction with chloroform. After washing withwater and drying, vacuum concentration was conducted. The residue waspurified by silica gel column chromatography (a n-hexane/ethyl acetatesystem) to give 3.20 g of the title compound as an oil (yield 96%).

¹ H-NMR(400 MHz, CDCl₃); δ (ppm) 1.30(6H, s), 3.45(3H, s), 3.80(2H, s),4.64 (2H, s), 4.74(2H, s), 7.34˜7.40(6H, m), 7.48(1H, ddd, J=8.5, 8.0,1.5 Hz), 7.73(1H, dd, J=8.0, 1.5 Hz)

FAB-MS; 326(MH⁺)

EXAMPLE 2

Synthesis of4,4-dimethyl-2-(4'-tetrahydropyranyloxymethyl-biphenyl-2-yl)oxazoline##STR70##

Tetrahybrofuran (15 ml) was added to 1.2 g (49.4 mmol) of flakymagnesium, followed by the addition of a small amount of dibromoethaneunder stirring. After the confirmation of bubbling, a solution of 11.0 g(40.6 mmol) of 4-bromobenzyl-tetrahydropyranyl ether in tetrahydrofuran(15 ml) was dropwise added thereto. After the confirmation of thedissolution of the magnesium, the resulting mixture was further stirredat room temperature for one hour. Then, a solution of 7.0 g (34.1 mmol)of 4,4-dimethyl-2-(2'-methoxyphenyl)oxazoline in tetrahydrofuran (5 ml)was dropwise added thereto, followed by stirring for 12 hours. Thereaction liquid was poured into a saturated aqueous solution of ammoniumchloride, followed by the extraction with chloroform. After washing withwater and drying, vacuum concentration was conducted. The residue waspurified by silica gel column chromatography (a n-hexane/ethyl acetatesystem) to give 6.61 g of the title compound as an oil (yield 53%).

¹ H-NMR(400 MHz, CDCl₃); δ (ppm) 1.29(6H, s), 1.50˜1.94(6H, m),3.52˜3.59(1H, m), 3.80(2H, s), 3.91˜3.97(1H, m), 4.55(1H, d, J=12.3 Hz),4.73(1H, t, J=3.7 Hz), 4.84(1H, d, J=12.3 Hz), 7.38(4H, s),7.34˜7.40(2H, m), 7.48(1H, ddd, J=8.0, 7.5, 1.5 Hz), 7.72(1H, ddd,J=8.0, 1.5, 1.0 Hz)

FAB-MS; 366(MH⁺)

EXAMPLE 3

Synthesis of 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline##STR71##

2.62 g (8.05 mmol) of4,4-dimethyl-2-(4'-methoxymethoxymethyl-biphenyl-2-yl)oxazoline wasdissolved in methanol (20 ml). 6N hydrochloric acid (10 ml) was addedthereto, followed by stirring at 40° C. for 2 hours. The reaction liquidwas poured into a saturated aqueous solution of sodiumhydrogen-carbonate, followed by the extraction with chloroform. Afterwashing with water and drying, vacuum concentration was conducted. Theresidue was purified by silica gel column chromatography (an-hexane/ethyl acetate system) to give 2.20 g of the title compound as acrystal (yield 97%).

m.p.; 97°˜100° C. ¹ H-NMR(400 MHz, CDCl₃); δ (ppm) 1.30(6H, s), 1.75(1H,br-s), 3.80(2H, s), 4.75(2H, s), 7.40(4H, s), 7.35˜7.42(2H, m), 7.48(1H,ddd, J=8.0, 7.5, 1.3 Hz), 7.73(1H, dd, J=8.1, 1.3 Hz)

EI-MS; 280 (M-H⁺)

EXAMPLE 4

Synthesis of 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline

4.0 g (10.9 mmol) of4,4-dimethyl-2-(4'-tetrahydropyranyloxymethyl-biphenyl-2-yl)oxazolinewas dissolved in methanol (50 ml), and 6N hydrochloric acid (15 ml) wasadded thereto, followed by stirring at room temperature for 2 hours. Thereaction liquid was poured into a saturated aqueous solution of sodiumhydrogencarbonate, followed by the extraction with chloroform. Afterwashing with water and drying, vacuum concentration was conducted. Theresidue was purified by silica gel column chromatography (an-hexane/ethyl acetate system) to give 3.0 g of the title compound(yield 98%).

EXAMPLE 5

Synthesis of 4,4-dimethyl-2-(4'-carboxybiphenyl-2-yl)oxazoline ##STR72##

20.0 g (75.4 mmol) of 4,4-dimethyl-2-(4'-methyl-biphenyl-2-yl)oxazolinewas dissolved in pyridine (75 ml) and water (150 ml), followed by theaddition of 71.4 g (452 mmol) of potassium permanganate in portionsunder reflux by heating. After the completion of the addition, theobtained mixture was further refluxed for 4 hours. The reaction liquidwas cooled and filtered to remove insolubles. After washing the residuewith hot water, the filtrates were combined and subjected to vacuumconcentration. The crystal which was precipitated by adding concentratedhydrochloric acid to the residue was recovered by filtration. 20.4 g ofthe title compound was obtained as a crystal (yield 92%).

m.p.; 190°-193° C. ¹ H-NMR(600 MHz, CDCl₃); δ (ppm) 1.16(6H, s),3.79(2H, s), 7.43˜7.48(4H, m), 7.49(1H, dr, J=7.5, 1.5 Hz), 7.58(1H, dd,J=7.5, 1.0 Hz), 7.96(2H, dd, J=8.6, 1.9 Hz), 12.90(1H, br)

FAB-MS; 296(MH⁺)

EXAMPLE 6

Synthesis of 4,4-dimethyl -2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline

1.28 g (33.7 mmol) of aluminum lithium hydride was suspended intetrahydrofuran (20 ml). At room temperature, 5.0 g (16.9 mmol) of4,4-dimethyl-2-(4'-carboxybiphenyl-2-yl)oxazoline was gradually addedthereto, followed by stirring for 2 hours. After the reaction liquid wascooled with ice, 100 ml of water was added thereto to conducthydrolysis, followed by the extraction with chloroform. After washingwith water and drying, vacuum concentration was conducted. The residuewas purified by silica gel column chromatography (a n-hexane/ethylacetate system) to give 4.2 g of the title compound (yield 88%).

EXAMPLE 7

Synthesis of 4,4-dimethyl-2-(4'-methoxycarbonylbiphenyl-2-yl)oxazoline##STR73##

10.0 g (33.8 mmol) of 4,4-dimethyl-2-(4'-carboxybiphenyl-2-yl)oxazolinewas dissolved in methylene chloride (200 ml). 4.8 g (40.8 mmol) ofthionyl chloride was added thereto, followed by stirring at roomtemperature for 2 hours. The reaction liquid was subjected to vacuumconcentration. Methanol (100 ml) was added to the residue, followed bystirring for 3 hours. After distilling out the solvent under a reducedpressure, methylene chloride and a saturated aqueous solution of sodiumhydrogencarbonate were added to the residue and obtained mixture wascaused liquid-liquid separation. After washing with water and drying,vacuum concentration was conducted. The residue was purified by silicagel column chromatography (an ethyl acetate/n-hexane system) to give9.53 g of the title compound as an oil (yield 91%)

¹ H-NMR(400 MHz, CDCl₃); δ (ppm) 1.26(6H, s), 3.77(2H, s), 3.92(3H, s),7.28˜7.56(5H, m), 7.75(1H, d, J=8.5 Hz), 8.03(2H, d, J=7.5 Hz)

FAB-MS; 310(MH⁺)

EXAMPLE 8

Synthesis of 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline

2.0 g (6.46 mmol) of4,4-dimethyl-2-(4'-methoxycarbonylbiphenyl-2-yl)oxazoline was dissolvedin tetrahydrofuran (20 ml). 0.49 g (12.9 mmol) of aluminum lithiumhydride was gradually added thereto under cooling with ice, followed bythe stirring for 2 hours as such. Water (50 ml) was added thereto toconduct hydrolysis, followed by the extraction with chloroform. Afterwashing with water and drying, vacuum concentration was conducted. Theresidue was purified by silica gel column chromatography (an-hexane/ethyl acetate system) to give 1.69 g of the title compound(yield 93%).

EXAMPLE 9

Synthesis of 4,4-dimethyl-2-(4'-chloromethyl-bipbenyl-2-yl)oxazoline##STR74##

1.0g (3.55 mmol) of4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline was dissolvedin methylene chloride (15 ml). Under cooling with ice, 0.51 g (4.29 mmol) of thionyl chloride was dropwise added thereto, followed by stirringfor one hour. The reaction liquid was poured into an aqueous solution ofsodium hydrogencarbonate, followed by the extraction with methylenechloride. After washing with water and drying, vacuum concentration wasconducted. 1.05 g of the title compound was obtained as a crystal (yield99%).

m.p.; 72°-75° C.

¹ H-NMR(400 MHz, CDCl₃); δ (ppm) 1.29(6H, s), 3.80(2H, s), 4.64(2H, s),7.35˜7.43(6H, m), 7.62(1H, td, J=7.6, 1.5 Hz ), 7.73(1H, ddd, J=7.6,1.5, 1.0 Hz ) FAB-MS; 300(MH⁺)

EXAMPLE 10

Synthesis of4,4-dimethyl-2-(4'-methanesulfonyloxymethyl-biphenyl-2yl)oxazoline##STR75##

2.0 g (7.1 mmol) of4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline and 1.43 g(14.1 mmol) of triethylamine were dissolved in methylene chloride (20ml). A solution of 0.98 g (8.6 mmol) of methanesulfonyl chloride inmethylene chloride (10 ml) was dropwise added thereto under cooling withsalt-ice. After stirring for 3 hours as such, the reaction liquid waspoured into water, followed by the extraction with methylene chloride.After washing with water and drying, vacuum concentration was conducted.2.53 g of the title compound was obtained as an oil (yield 99%).

¹ H-NMR (90 MHz, CDCl₃); δ (ppm) 1.31(6H, s), 2.94(3H, s), 3.80(2H, s),6.26(2H, s), 7.40(4H, s), 7.14˜7.80(4H, m)

EXAMPLE 11

Synthesis of4,4-dimethyl-2-(4'-p-toluenesulfonyloxymethyl-biphenyl-2-yl)oxazoline##STR76##

0.34 g (8.5 mmol) of a 60% oily sodium hydride was suspended intetrahydrofuran (20 ml). A solution of 2.0 g (7.1 mmol) of4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline intetrahydrofuran (30 ml) was dropwise added thereto at room temperature,followed by further stirring at room temperature for one hour. After thereaction liquid was cooled with ice, a solution of 1.6 g (8.4 mmol) ofp-toluenesulfonyl chloride in tetrahydrofuran (20 ml) was dropwise addedthereto. After stirring for 3 hours as such, the reaction liquid waspoured into a saturated aqueous solution of ammonium chloride, followedby the extraction with chloroform. After washing with water and drying,vacuum concentration was conducted. The residue was purified by silicagel column chromatography (a n-hexane/ethyl acetate system) to give 1.7g of the title compound as an oil (yield 55%).

¹ H-NMR(90 MHz, CDCl₃); δ (ppm) 1.28(6H, s), 2.24(3H, s), 3.76(2H, s),5.07(2H, s), 7.11˜7.70(10H, m), 7.78(2H, d, J=8 Hz)

FAB-MS; 436(MH⁺)

EXAMPLE 12

Synthesis of 2-(4'-hydroxymethylphenyl)benzoic acid ##STR77##

2.0 g (7.11 mmol) of4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline was dissolvedin methylene chloride (10 ml). 3.0 g (21.1 mmol) of methyl iodide wasadded thereto, followed by stirring for 12 hours. After the reactionliquid was concentrated to dryness, methanol (20 ml) and a 20% aqueoussolution of sodium hydroxide (20 ml) was added thereto, followed byheating under reflux for 13 hours. After cooling to room temperature andadjusting to pH 6 with hydrochloric acid, the resulting mixture wasextracted with chloroform. After washing with water and drying, vacuumconcentration was conducted. The residue was purified by silica gelcolumn chromatography (a chloroform/methanol system) to give 1.24 g ofthe title compound as a crystal (yield 77%).

m.p.; 140°-142° C.

¹ H-NMR(90 MHz, CDCl₃); δ (ppm) 4.70(2H, s), 5.25(1H, br-s),7.20-7.62(7H, m), 7.90(1H, dd, J=7.6, 1.5 Hz)

FAB-MS; 228(M⁺)

EXAMPLE 13

Synthesis of 2-(4'-hydroxymethylphenyl)benzoic acid

2.0 g (7.11 mmol) of4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline was dissolvedin ethanol (30 ml). 2N hydrochloric acid (10 ml) was added thereto,followed by heating under reflux for 8 hours. After the reaction liquidwas cooled and concentrated, a saturated aqueous solution of sodiumhydrogen-carbonate (100 ml) was added thereto, followed by theextraction with chloroform. After the organic phase was washed withwater and dried, it was subjected to vacuum concentration. A 20% aqueoussolution of sodium hydroxide (20 ml) and ethanol (20 ml) were added tothe residue, followed by heating under reflux for 8 hours. After thereaction liquid was cooled to room temperature and adjusted to pH 6 withhydrochloric acid, it was extracted with chloroform. After the organicphase was washed with water and dried, it was subjected to vacuumconcentration. The residue was purified by silica gel columnchromatography (a chloroform/methanol system) to give 1.31 g of thetitle compound (yield 81%).

EXAMPLE 14

Synthesis of 2-(4'-bydroxymethylpbenyl)benzoic acid

Water (6 ml) and sulfuric acid (3.6 g) were added to 2.0 g (7.11 mmol)of 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline, followed byheating under reflux for 30 hours. After the reaction liquid was cooled,it was neutralized with a 10% aqueous solution of sodium hydroxide andextracted with chloroform. After the organic phase was washed with waterand dried, it was subjected to vacuum concentration. The residue waspurified by silica gel column chromatography (a chloroform/methanolsystem) to give 1.05 g of the title compound (yield 65%).

EXAMPLE 15

Synthesis of methyl 2-(4'-hydroxymethylphenyl)benzoate ##STR78##

4.0 g (17.5 mmol) of 2-(4'-hydroxymethylphenyl)benzoic acid wasdissolved in methanol (50 ml). Sulfuric acid (1 ml) was added thereto,followed by heating under reflux for 8 hours. After conducting vacuumconcentration, water was added thereto, followed by the extraction withchloroform. After the organic phase was washed with water and dried, itwas subjected to vacuum concentration. The residue was purified bysilica gel column chromatography (a n-hexane/ethyl acetate system) togive 3.8 g of the title compound as an oil (yield 89%).

¹ H-NMR(400 MHz, CDCl₃); δ (ppm) 1.60(1H, br-s), 3.64(3H, s), 4.72(2H,s), 7.29(2H, d, J=8.0 Hz), 7.33(1H, dd, J=7.7, 1.4 Hz), 7.38(1H, td,J=7.7, 1.4 Hz), 7.39(2H, d, J=8.0 Hz), 7.51(1H, td, J=7.7, 1.4 Hz),7.81(1H, dd, J=7.7, 1.4 Hz)

FAB-MS; 242(M⁺)

EXAMPLE 16

Synthesis of methyl 2-(4'-methanesulfonyloxymethylphenyl)benzoate##STR79##

10.0 g (41 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate and 8.4 g(83.0 mmol) of triethylamine were dissolved in methylene chloride (150ml). Under cooling with ice, a solution of 5.7 g (50 mmol) ofmethanesulfonyl chloride in methylene chloride (25 ml) was dropwiseadded thereto, followed by further stirring for one hour. The reactionliquid was poured into water, followed by the extraction with methylenechloride. After the organic phase was washed with water and dried, itwas subjected to vacuum concentration. 13.1 g of the title compound wasobtained as a wax (yield 100%).

m.p.; 43°-45° C.

¹ H-NMR(90 MHz, CDCl3); δ (ppm) 2.96(3H, s), 3.64(3H, s), 5.25(2H, s),7.20-7.60(7H, m), 7.72-7.90(1H, m)

EXAMPLE 17

Synthesis of methyl 2-(4'-p-toluenesulfonyloxymethylpbenyl)benzoate##STR80##

10.0 g (41 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate wasdissolved in tetrahydrofuran (200 ml). 2.0 g (50 mmol) of a 60% sodiumhydride was added thereto under cooling with ice, followed by stirringfor one hour. A solution of 8.65 g (45.4 mmol) of p-toluenesulfonylchloride in tetrahydrofuran (50 ml) was dropwise added thereto. Then,the reaction was effected at room temperature for 2 hours and furtherreflux by heating was effected for 4 hours. The reaction liquid wascooled and added to a saturated aqueous solution of ammonium chloride.The resulting mixture was extracted with chloroform (200 ml). After theorganic phase was washed with water and dried, it was subjected tovacuum concentration. The residue was purified by silica gel columnchromatography (a n-hexane/ethyl acetate system) to give 13.4 g of thetitle compound as a wax (yield 82%).

¹ H-NMR(90 MHz, CDCl₃); δ (ppm) 2.44(3H, s), 3.60(3H, s), 5.07(2H, s),7.23(4H, s), 7.34(2H, d, J=7.7 Hz), 6.96-7.60 (3H, m), 7.77(2H, d, J=7.7Hz), 7.64-7.90(1H, m)

EXAMPLE 18

Synthesis of methyl 2-(4'-bromomethylphenyl)benzoate ##STR81##

10.0 g (41 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate wasdissolved in 7.9 g of pyridine and n-hexane (100 ml). 8.3 g (31 mmol) ofphosphorus tribromide was dropwise added thereto under cooling with ice,followed by stirring for 2 hours as such. The reaction liquid was addedto an aqueous solution of sodium hydrogencarbonate, followed by theextraction with n-hexane. The organic phase was washed with water, driedand subjected to vacuum concentration. The residue was purified bysilica gel column chromatography (a n-hexane/ethyl acetate system) togive 9.5 g of the title compound (yield 75%).

m.p.; 50°-51° C.

¹ H-NMR(90 MHz, CDCl3); δ (ppm) 3.62(3H, s), 5.01(2H, s), 7.12-7.60(7H,m), 7.68-7.85(1H, m)

FAB-MS; 305, 307(MH⁺)

EXAMPLE 19

Synthesis of methyl 2-(4'-bromomethylphenyl)benzoate

2.0 g (8.8 mmol) of methyl 2-(4'-methylphenyl)benzoate, 1.6 g (9.0 mmol)of N-bromosuccinimide and 0.05 g of α,α'-azobis(isobutyronitrile)[another name; 2,2'-azobis(isobutyronitrile)] were dissolved in carbontetrachloride (110 ml), followed by heating under reflux for 2 hours.The resultant mixture was filtered to remove insolubles, and then vacuumconcentration was effected. The residue was recrystallized from an-hexane/isopropyl ether mixed solvent to give 1.6 g of the titlecompound (yield; 59%).

EXAMPLE 20

Synthesis of methyl 2-(4'-chloromethylpbenyl)benzoate ##STR82##

4.8 g (40.3 mmol) of thionyl chloride was dropwise added to a solutionof 5.0 g (20.6 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate inmethylene chloride (50 ml) under cooling with ice. After the completionof the dropwise adding, the obtained mixture was brought to roomtemperature and stirred for 4.5 hours. After a saturated aqueoussolution (150 ml) of sodium hydrogencarbonate was dropwise added to thereaction liquid, the obtained mixture was extracted twice with ethylacetate (150 ml, 100 ml). The organic phases were combined and washedwith water. The resultant organic phase was dried over anhydrousmagnesium sulfate and subjected to vacuum concentration to give 5.8 g ofan oily residue. This crude product was purified by silica gel columnchromatography (a n-hexane/ethyl acetate system) to give 4.9 g of thetitle compound (yield; 91%).

¹ H-NMR(400 MHz, CDCl₃): δ (ppm) 3.65(3H, s), 4.64(2H, s), 7.30(2H, d,J=7.5 Hz), 7.36(1H, dd, J=7.8, 1.5 Hz), 7.40-7.44(3H, m), 7.53(1H, td,J=7.8, 1.4 Hz), 7.85(1H, d, J=8.3 Hz)

FAB-MS: 261(MH⁺)

EXAMPLE 21

Synthesis of methyl 2-(4'-chloromethylphenyl)benzoate

2.0 g (8.25 mmol) of methyl 2-(4'-hydroxymethylphenyl)benzoate wasdissolved in 1.31 g of pyridine and methylene chloride (20 ml). 1.47 g(12.4 mmol) of thionyl chloride was dropwise added thereto at roomtemperature, followed by stirring as such for 16 hours and under refluxby heating for 5 hours. After the reaction liquid was cooled andconcentrated, a saturated aqueous solution of sodium hydrogencarbonatewas added thereto, followed by the extraction with methylene chloride.The organic phase was washed with water, dried and subjected to vacuumconcentration. The residue was purified by silica gel columnchromatography (a n-hexane/ethyl acetate system) to give 1.89 g of thetitle compound as an oil (yield 88%).

EXAMPLE 101

Synthesis of 2-cyclopropanecarboxamido-5-bromo-4-methyl -3-nitropyridine##STR83##

A mixture comprising 10 g (43.1 mmol) of2-amino-5-bromo-4-methyl-3-nitropyridine, 6.3 g of4-dimethylaminopyridine and xylene (50 ml) was heated at 110° C. in anitrogen atmosphere. 5 g (47.4 mmol) of cyclopropanecarbonyl chloridewas dropwise added thereto, followed by further stirring at 110° C. for2 hours. The reaction mixture was brought to room temperature, followedby the addition of dichloromethane (200 ml) and water (50 ml). Theorganic phase was separated and the aqueous phase was further extractedwith dichloromethane (50 ml). The organic phases were combined andwashed with water (50 ml). The resulting organic phase was dried overanhydrous magnesium sulfate and concentrated to give a crude crystal. Itwas recrystallized from chloroform/ethyl acetate to give 11.4 g of thetitle compound (yield 88%).

m.p.; 204.7° C.

¹ H-NMR (400 MHz, CDCl₃); δ (ppm) 0.91˜0.96 (2H, m), 1.12˜1.16 (2H, m),1.59˜1.71 (1H, m), 2.52(3H, s), 8.21(1H, br-s), 8.58 (1H, S)

FAB-MS; 300, 302 (MH⁺)

EXAMPLE 102

synthesis of 2-cyclopropanecarboxamido-4-methyl-3-nitropyridine##STR84##

A mixture comprising 5.0 g (32.6 mmol) of2-amino-4-methyl-3-nitropyridine and 5.2 g of pyridine was heated at110° C. in a nitrogen atmosphere. 3.8 g (36 mmol) ofcyclopropanecarbonyl chloride was dropwise added thereto, followed byfurther stirring at 110° C. for 5 hours. The reaction mixture wasbrought to room temperature, followed by the addition of chloroform (50ml) and water (50 ml). The organic phase was separated and the aqueousphase was further extracted with chloroform (50 ml) twice. The organicphases were combined and washed with water (20 ml) and a saturatedaqueous solution (20 ml) of common salt, successively. The resultantorganic phase was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (a n-hexane/ethyl acetate system) to give 5.4 g of thetitle compound (yield 75%).

m.p.; 179° C.

¹ H-NMR (400 MHz, CDCl₃); δ (ppm) 0.89˜0.94 (2H, m), 1.11˜1.15 (2H, m),1.67˜1.73 (1H, m), 2.49 (3H, d, J=0.6 Hz), 7.08 (1H, dd, J=5.0, 0.6 Hz),8.36 (1H, d, J=5.0 Hz), 8.61 (1H, br-s)

FAB-MS; 222 (MH⁺)

EXAMPLE 103

Synthesis of 2-cyclopropanecarboxamido-4-methyl-3-nitropyridine

Toluene (60 ml) was added to 3.0 g (10.0 mmol) of5-bromo-2-cyclopropanecarboxamido-4-methyl-3-nitropyridine, 10% Pd--C(100 mg) and 2.9 g (28.6 mmol) of triethylamine, followed by stirringand heating under reflux. 1.9 g (41.3 mmol) of formic acid was dropwiseadded to this solution, followed by stirring for 5 hours. The reactionliquid was brought to room temperature and filtered to remove thecatalyst. The filtrate was subjected to vacuum concentration. Chloroform(100 ml) and water (100 ml) were added to the residue and the obtainedmixture was caused liquid-liquid separation. The aqueous phase wasfurther extracted with chloroform (50 ml) once. The organic phases werecombined, dried over anhydrous magnesium sulfate'and subjected to vacuumconcentration. The residue was purified by silica gel columnchromatography (a n-hexane/ethyl acetate system) to give 1.6 g of thetitle compound (yield 72).

EXAMPLE 104

Synthesis of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine##STR85##

0.95 g (3.17 mmol) of2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine was added toa solution of 0.40 g (3.56 mmol) of potassium t-butoxide intetrahydrofuran (15 ml), followed by stirring at room temperature for 30minutes. Then, this solution was heated, and a solution of 0.91 g (3.49g) of methyl 2-(4'-chloromethylphenyl)benzoate in tetrahydrofuran (10ml) was dropwise added thereto under reflux. After the completion of thedropwise addition, the obtained mixture was stirred under reflux for 23hours. The reaction liquid was brought to room temperature, and asaturated aqueous solution (30 ml) of ammonium chloride and ethylacetate (20 ml) were added thereto to conduct extraction. The aqueousphase was further extracted twice with ethyl acetate (20 ml×2). Theorganic phases were combined, washed with water and dried over anhydrousmagnesium sulfate, and then subjected to vacuum concentration to give1.25 g of an oily residue. This crude product was purified by silica gelcolumn chromatography (a n-hexane/ethyl acetate system) to give 1.01 gof the title compound (yield; 61%).

¹ H-NMR(600 MHz, CDCl₃); δ (ppm) 0.70˜0.85(2H, br), 1.00˜1.20(2H, br),1.56(1H, br), 2.43(3H, s), 3.60(3H, s), 5.00˜5.40(2H, br), 7.00˜7.45(4H,br), 7.33(1H, dd, J=7.7, 1.1 Hz), 7.37(1H, ddd, J=7.7, 7.7, 1.1 Hz),7.49(1H, ddd, J=7.7, 7.7, 1.1 Hz), 7.78(1H, dd, J=7.7, 1.1 Hz), 8.67(1H,s)

FAB-MS; 524, 526 (MH⁺)

EXAMPLE 105

Synthesis of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine

7.0 g (23 mmol) of2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine was added toa solution of 3.14 g (28 mmol) of potassium t-butoxide intetrahydrofuran (80 ml), followed by stirring at room temperature forone hour. Then, this solution was heated. A solution of 8.5 g (28 mmol)of methyl 2-(4'-bromomethylphenyl)benzoate in tetrahydrofuran (50 ml)was dropwise added thereto under reflux by heating, followed by stirringfor 1.5 hours after the completion of the dropwise addition. Thereaction mixture was brought to room temperature. Ethyl acetate (200 ml)and a saturated aqueous solution (100 ml) of ammonium chloride wereadded thereto to conduct extraction. The aqueous phase was furtherextracted with ethyl acetate (100 ml) twice. The organic phases werecombined and washed with a saturated aqueous solution of common salt.The resultant organic phase was dried over anhydrous magnesium sulfateand subjected to vacuum concentration to give 13.3 g of an oilysubstance. This crude substance was purified by silica gel columnchromatography (a n-hexane/ethyl acetate system) to give 9.2 g of thetitle compound (yield 75%).

EXAMPLE 106

Synthesis of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine

6.0 g (20 mmol) of2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine was added toa solution of 2.47 g (22 mmol) of potassium t-butoxide intetrahydrofuran (100 ml), followed by stirring at room temperature forone hour. A solution of 7.0 g (22 mmol) of methyl2-(4'-methanesulfonyloxymethylphenyl)benzoate in tetrahydrofuran (60 ml)was dropwise added thereto under reflux by heating, followed by thereaction as such for 3 hours. The reaction liquid was cooled and addedto a saturated aqueous solution of ammonium chloride, followed by theextraction with chloroform. After the organic phase was washed withwater and dried, it was subjected to vacuum concentration. The residuewas purified by silica gel column chromatography (a n-hexane/ethylacetate system) to give 8.4 g of the title compound (yield 80%).

EXAMPLE 107

Synthesis of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine

7.5 g (25 mmol) of2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine was added toa solution of 3.14 g (28 mmol) of potassium t-butoxide intetrahydrofuran (100 ml), followed by stirring at room temperature for45 minutes. A solution of 11.1 g (28 mmol) of methyl2-(4'-p-toluenesulfonyloxymethylphenyl)benzoate in tetrahydrofuran (50ml) was dropwise added thereto under reflux by heating, followed by thereaction as such for 4 hours. After the reaction liquid was cooled, itwas added to a saturated aqueous solution of ammonium chloride, followedby the extraction with chloroform. After the organic phase was washedwith water and dried, it was subjected to vacuum concentration. Theresidue was purified by silica gel column chromatography (an-hexane/ethyl acetate system) to give 11.3 g of the title compound(yield 86%).

EXAMPLE 108

Synthesis of2-[N-cyclopropanecarbonyl-N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4-methyl-3-nitropyridine ##STR86##

1.80 g (6.0 mmol) of2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine was added toa solution of 0.08 g (7.1 mmol) of potassium t-butoxide intetrahydrofuran (15 ml). After stirring at room temperature for onehour, 0.45 g (3.0 mmol) of sodium iodide and N,N-dimethylformamide (10ml) were added thereto. Then, a solution of 2.50 g (8.3 mmol) of4,4-dimethyl-2-(4'-chloromethyl-biphenyl-2-yl)oxazoline intetrahydrofuran (20 ml) was dropwise added thereto under reflux byheating, followed by stirring as such for 13 hours. The reaction liquidwas cooled and added to a saturated aqueous solution of ammoniumchloride, followed by the extraction with chloroform. After washing withwater and drying, vacuum concentration was conducted. The residue waspurified by silica gel column chromatography (a n-hexane/ethyl acetatesystem) to give 2.73 g of the title compound (yield 81%).

¹ H-NMR (400 MHz, CDCl₃); δ (ppm) 0.74˜0.79 (2H, m), 1.07˜1.12 (2H, m),1.23 (6H, s), 1.55˜1.65 (1H, m), 2.43 (3H, s), 3.77 (2H, s), 4.50˜5.40(2H, br), 7.25˜7.40 (6H, m), 7.46 (1H, td, J=8.0, 1.0 Hz), 7.72 (1H, d,J=8.0 Hz), 8.66 (1H, s)

FAB-MS; 563, 565 (MH⁺)

EXAMPLE 109

Synthesis of2-[N-cyclopropanecarbonyl-N-{2'-[4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4-methyl-3-nitropyridine

1.52 g (5.1 mmol) of2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine was added toa solution of 0.74 g (6.6 mmol) of potassium t-butoxide intetrahydrofuran (10 ml), followed by stirring at room temperature for 1hour. Then, a solution of 2.4 g (6.7 mmol) of4,4-dimethyl-2-(4'-methanesulfonyloxy-methyl-biphenyl-2-yl)oxazoline indimethylsulfoxide (10 ml) was dropwise added thereto under reflux byheating, followed by stirring as such for 3 hours. The reaction mixturewas cooled and added to a saturated aqueous solution of ammoniumchloride, followed by the extraction with chloroform. After washing withwater and drying, vacuum concentration was conducted. The residue waspurified by silica gel column chromatography (a n-hexane/ethyl acetatesystem) to give 1.26 g of the title compound (yield 44).

EXAMPLE 110

Synthesis of2-[N-cyclopropanecarbonyl-N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4-methyl-3-nitropyridine

1.50 g (5.0 mmol) of2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine was added toa solution of 0.67 g (6.0 mmol) of potassium t-butoxide intetrahydrofuran (10 ml), followed by stirring at room temperature for 45minutes. Then, a solution of 2.60 g (6.0 mmol) of4,4-dimethyl-2-(4'-p-toluenesulfonyl-oxymethyl-biphenyl-2-yl)oxazolinein tetrahydrofuran (20 ml) was dropwise added thereto under reflux byheating, followed by stirring as such for 4 hours. The reaction liquidwas cooled and poured into a saturated aqueous solution of ammoniumchloride, followed by the extraction with chloroform. The aqueous phasewas further extracted with chloroform (100 ml) twice. After washing withwater and drying, vacuum concentration was conducted. The residue waspurified by silica gel column chromatography (an ethyl acetate/n-hexanesystem) to give 1.40 g of the title compound (yield 50%).

EXAMPLE 111

Synthesis of2-[N-cyclopropanecarbonyl-N-{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}-methyl]amino-5-bromo-4-methyl-3-nitropyridine

1.5 g (5.0 mmol) of2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine, 1.4 g (5.0mmol) of 4,4-dimethyl-2-(4'-hydroxymethyl-biphenyl-2-yl)oxazoline and0.89 g (5.0 mmol) of diethyl azodicarboxylate were dissolved intetrahydrofuran (30 ml). After cooling to -70° C. and stirring for 2hours, a solution of 1.3 g (5.0 mmol) of triphenylphosphine intetrahydrofuran (20 ml) was dropwise added thereto. After stirring assuch at -70° C. for 2 hours, it was stirred at room temperature for 12hours and further at 50° C. for 5 hours. The solvent was distilled offunder a reduced pressure, ether (10 ml) was added to the residue, andthe crystal thus precipitated was filtered out. The filtrate wassubjected to vacuum concentration. The residue was purified by silicagel column chromatography (a n-hexane/ethyl acetate system) to give 2.0g of the title compound (yield 71%).

EXAMPLE 112

Synthesis of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-4-methyl-3-nitropyridine##STR87##

2.0 g (9 mmol) of 2-cyclopropanecarboxamido-4-methyl-3-nitropyridine wasadded to a solution of 1.23 g (11 mmol) of potassium t-butoxide intetrahydrofuran (30 ml), followed by stirring at room temperature forone hour. Then, this solution was heated, and a solution of 8.5 g (28mmol) of methyl 2-(4'-bromomethylphenyl)benzoate in tetrahydrofuran (20ml) was dropwise added thereto under reflux, followed by stirring for 2hours after the completion of the dropwise addition. The reactionmixture was brought to room temperature, and chloroform (200 ml) and asaturated aqueous solution of ammonium chloride (200 ml) were addedthereto to conduct extraction. The aqueous phase was further extractedwith chloroform (50 ml) twice. The organic phases were combined, driedover anhydrous magnesium sulfate and subjected to vacuum concentration.The residue was purified by silica gel column chromatography (an-hexane/ethyl acetate system) to give 3.4 g of the title compound(yield 84%).

¹ H-NMR (600 MHz, CDCl₃); δ (ppm) 0.62˜0.75 (2H, br), 0.98˜1.11 (2H,br), 1.51 (1H, br-s), 2.36 (3H, s), 3.55 (3H, s), 5.10 (2H, br-s),7.00˜7.34 (5H, m), 7.28 (1H, d, J=7.5 Hz), 7.32 (1H, dd, J=7.5, 7.5 Hz),7.43 (1H, dd, J=7.5, 7.5 Hz), 7.72 (1H, d, J=7.5 Hz), 8.42 (1H, br-s)

FAB-MS; 446 (MH⁺)

EXAMPLE 113

Synthesis of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-4-methyl-3-nitropyridine

Toluene (100 ml) was added to 5.0 g (9.53 mmol) of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine,10% Pd--C (100 mg) and 2.9 g (28.6 mmol) of triethylamine, followed byheating under reflux with stirring. 0.7 g (15.2 mmol) of formic acid wasdropwise added thereto, followed by stirring for 5 hours. The reactionliquid was brought to room temperature and filtered to remove thecatalyst. Then, the filtrate was subjected to vacuum concentration.Chloroform (200 ml) and water (200 ml) were added to the residue and theobtained mixture was caused liquid-liquid separation. The aqueous phasewas further extracted with chloroform (100 ml) once. The organic phaseswere combined, dried over anhydrous magnesium sulfate and subjected tovacuum concentration. The residue was purified by silica gel columnchromatography (a n-hexane/ethyl acetate system) to give 3.6 g of thetitle compound (yield 85%).

EXAMPLE 114

Synthesis of 2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-7-methyl-3-H-imidazo[4,5-b]pyridine ##STR88##

Ethanol (25 ml) was added to 1.0 g (1.9 mmol) of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine,iron (1.0 g) and acetic acid (2.5 ml), followed by stirring underheating at 80° C. for one hour. The reaction liquid was brought to roomtemperature and filtered to remove insolubles. The filtrate wassubjected to vacuum concentration. Chloroform (50 ml) and water (25 ml)were added to the residue and the obtained mixture was causedliquid-liquid separation. The aqueous phase was further extracted withchloroform (50 ml) once. After the organic phases were combined andwashed with an aqueous solution (25 ml) of sodium hydrogencarbonate, theresultant organic phase was dried over anhydrous magnesium sulfate andsubjected to vacuum concentration. The residue was purified by silicagel column chromatography (a n-hexane/chloroform system) to give 0.54 gof the title compound (yield 59%).

¹ H-NMR (600 MHz, CDCl₃); δ (ppm) 0.98˜1.01 (2H, m),

1.14˜1.16 (2H, m), 1.86˜1.91 (1H, m), 2.59 (3H, s), 3.54 (3H, s), 5.51(2H, s), 7.14 (2H, d, J=8.4 Hz), 7.17 (2H, d, J=8.4 Hz ), 7.22 (1H, dd,J=7.5, 1.1 Hz), 7.32 (1H, ddd, J=7.5, 7.5, 1.1 Hz), 7.44 (1H, ddd,J=7.5, 7.5, 1.1 Hz), 7.74 (1H, dd, J=7.5, 1.1 Hz), 8.28 (1H, s)

FAB-MS; 446, 448 (MH⁺) EXAMPLE 115

Synthesis of3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4-methylpyridine##STR89##

Methanol (50 ml) was added to 1.0 g (1.9 mmol) of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine,activated carbon (200 mg), 400 mg (7.99 mmol) of hydrazine monohydrateand 2.16 g (7.99 mmol) of ferric chloride hexahydrate, followed byheating under reflux with stirring for 16 hours. The reaction solutionwas brought to room temperature and filtered through Celite to removeinsolubles. After the filtrate was subjected to vacuum concentration,chloroform (200 ml) and water (100 ml) were added to the residue and theobtained mixture was caused liquid-liquid separation. The aqueous phasewas further extracted with chloroform (100 ml) twice. The organic phaseswere combined, dried over anhydrous magnesium sulfate and subjected tovacuum concentration. The residue was purified by silica gel columnchromatography (a n-hexane/chloroform system) to give 0.65 g of thetitle compound (yield 69%).

¹ H-NMR (600 MHz, CDCl₃); δ (ppm) 0.78˜0.80 (4H, m), 1.83˜1.88 (1H, m),2.07 (3H, s), 3.58 (3H, s), 4.57 (2H, d, J=6.1 Hz), 6.73 (1H, t, J=6.1Hz), 7.19 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 7.39 (1H, dd,J=7.6, 1.2 Hz), 7.45 (1H, ddd, J=7.6, 7.6, 1.2 Hz), 7.58 (1H, ddd,J=7.6, 7.6, 1.2 Hz), 7.69 (1H, dd, J=7.6, 1.2 Hz), 7.98 (1H, s), 9.47(1H, s)

FAB-MS; 494, 496 (MH⁺)

EXAMPLE 116

Synthesis of 2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-7-methyl-3-H-imidazo[4,5-b]pyridine

Toluene (20 ml ) was added to 600 mg(1.21 mmol) of3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4-methylpyridine,100 mg of p-toluenesulfonic acid monohydrate and molecular sieves 4A(500 mg), followed by heating under reflux with stirring for 2 hours.The reaction solution was brought to room temperature and filteredthrough Celite to remove insolubles. Chloroform (20 ml) and an aqueoussolution (50 ml) of sodium hydrogencarbonate were added to the filtrateand the obtained mixture was caused liquid-liquid separation. Theaqueous phase was further extracted with chloroform (20 ml) twice. Theorganic phases were combined, dried over anhydrous magnesium sulfate andsubjected to vacuum concentration. The residue was purified by silicagel column chromatography (a n-hexane/ethyl acetate system) to give 400mg of the title compound (yield 69%).

EXAMPLE 117

Synthesis of2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine##STR90##

Toluene (20 ml) was added to 1.0 g (1.9 mmol) of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine,10% Pd--C (40 mg) and 2.9 g (29 mmol) of triethylamine, followed byheating under reflux with stirring. 1.0 g (22 mmol) of formic acid wasdropwise added thereto, followed by stirring for 7 hours. The reactionliquid was brought to room temperature and filtered to remove thecatalyst, and then the filtrate was subjected to vacuum concentration.Chloroform (50 ml) and water (20 ml) were added to the residue and theobtained mixture was caused liquid-liquid separation. The aqueous phasewas further extracted with chloroform (20 ml) twice. The organic phaseswere combined, dried over anhydrous magnesium sulfate and subjected tovacuum concentration. The residue was purified by silica gel columnchromatography (a n-hexane/chloroform system) to give 0.65 g of thetitle compound (yield 86%).

¹ H-NMR (90 MHz, CDCl₃); δ (ppm) 0.82˜1.30 (4H, m), 1.80˜2.10 (1H, m),2.64 (3H, s), 3.60 (3H, s), 5.62 (2H, s), 6.98 (1H, d, J=5.0 Hz), 7.22(4H, s), 7.10˜7.56 (3H, m), 7.63˜7.85 (1H, m), 8.16 (1H, d, J=5.0 Hz)

FAB-MS 398 (MH⁺)

EXAMPLE 118

Synthesis of2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

Ethanol (50 ml) was added to 1.0 g (1.9 mmol) of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine,10% Pd--C (100 mg), 0.4 g (3.9 mmol) of triethylamine and acetic acid (5ml), followed by conducting hydrogenation under normal pressure for 22hours. After the removal of the catalyst by filtration, the filtrate wassubjected to vacuum concentration. Chloroform (100 ml) and an aqueoussolution (100 ml) of sodium hydrogencarbonate were added to the residueand the obtained mixture was caused liquid-liquid separation. Theaqueous phase was further extracted with chloroform (100 ml) twice. Theorganic phases were combined, dried over anhydrous magnesium sulfate andsubjected to vacuum concentration. The residue was purified by silicagel column chromatography (a n-hexane/ethyl acetate system) to give 0.61g of the title compound (yield: 80%).

EXAMPLE 119

Synthesis of2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

i-Propanol (100 ml) was added to 1.0 g (1.9 mmol) of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine,1.5 g (39 mmol) of sodium borohydride and 2.2 g (12.9 mmol) of cupricchloride dihydrate, followed by stirring under heating at 60° C. for 6hours. The reaction liquid was brought to room temperature and filteredto remove insolubles, and then the filtrate was subjected to vacuumconcentration. Chloroform (200 ml) and water (100 ml) were added to theresidue and the obtained mixture was caused liquid-liquid separation.The aqueous phase was extracted with chloroform (50 ml) twice. Theorganic phases were combined, dried over anhydrous magnesium sulfate andsubjected to vacuum concentration. The residue was purified by silicagel column chromatography (a n-hexane/chloroform system) to give 0.43 gof the title compound (yield 57%).

EXAMPLE 120

Synthesis of 2-cyclopropyl -3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

Tetrahydrofuran (100 ml) was added to 1.0 g (1.9 mmol) of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5bromo-4-methyl-3-nitropyridine and 10% Pd--C (400 mg), followed bystirring. A 30% aqueous solution (20 ml) of sodium hypophosphite wasdropwise added to this solution at room temperature in one hour,followed by further stirring at 60° C. for 2 hours. The reaction liquidwas brought to room temperature and filtered to remove the catalyst, andthen the filtrate was subjected to vacuum concentration. Chloroform (50ml) and water (20 ml) were added to the residue and the obtained mixturewas caused liquid-liquid separation. The aqueous phase was furtherextracted with chloroform (20 ml) twice. The organic phases werecombined, dried over anhydrous magnesium sulfate and subjected to vacuumconcentration. The residue was purified by. silica gel columnchromatography (a n-hexane/chloroform system) to give 0.35 g of thetitle compound (yield 46%).

EXAMPLE 121

Synthesis of 2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

Ethanol (100 ml) was added to 1.0 g (1.9 mmol) of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine,10% Pd--C (50 mg), 2.0 g (35.8 mmol) of powdered iron and 10 ml (175mmol) of acetic acid, followed by heating under reflux for 11 hours. Thereaction liquid was brought to room temperature and filtered to removeinsolubles, and then the filtrate was subjected to vacuum concentration.Chloroform (200 ml) and water (100 ml) were added to the residue and theobtained mixture was caused liquid-liquid separation. The aqueous phasewas extracted with chloroform (50 ml) twice. The organic phases werecombined, dried over anhydrous magnesium sulfate and subjected to vacuumconcentration. The residue was purified by silica gel columnchromatography (a n-hexane/chloroform system) to give 0.46 g of thetitle compound (yield 61%).

EXAMPLE 122

Synthesis of2-cyclopropyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-7-methyl-3H-imidazo[4,5-b]pyridine##STR91##

1.71 g (3.0 mmol) of2-[N-cyclopropanecarbonyl-N{2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl}methyl]amino-5-bromo-4-methyl-3-nitropyridinewas dissolved in toluene (100 ml), followed by the addition of 104%Pd-carbon catalyst (100 mg), 5.8 g (57.3 mmol) of triethylamine and 1.40g (30.4 mmol) of formic acid. The obtained mixture was heated underreflux for 10 hours. The reaction liquid was cooled and filtered toremove the catalyst, and then the filtrate was subjected to vacuumconcentration. Chloroform and water were added to the residue to conductextraction. After washing with water and drying, vacuum concentrationwas conducted. The residue was purified by silica gel columnchromatography (a n-hexane/ethyl acetate system) to give 1.02 g of thetitle compound (yield 77%).

¹ H-NMR (400 MHz, CDCl₃); δ (ppm) 1.02˜1.12 (4H, m), 1.24 (6H, s),1.93˜2.01 (1H, m), 2.66 (3H, s), 3.47 (2H, s), 5.62 (2H, s), 7.03 (1H,d, J=7.2 Hz), 7.23 (2H, d, J=8.0 Hz), 7.30˜7.35 (1H, m), 7.32 (2H, d,J=8.0 Hz), 7.36 (1H, td, J=8.0, 1.0 Hz), 7.47 (1H, td, J=8.0, 1.0 Hz),7.73 (1H, d, J=8.0 Hz), 8.22 (1H, d, J=7.2 Hz)

FAB-MS; 437 (MH⁺)

EXAMPLE 123

Synthesis of 2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo]4,5-b]pyridine

Ethanol (100 ml) was added to 2.06 g (4.6 mmol) of2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]cyclopropanecarboxamido-4-methyl-3-nitropyridine,2.56 g (46.0 mmol) of powdered iron and 5 ml (87 mmol) of acetic acid,followed by stirring under heating at 80° C. for 4 hours. The reactionliquid was brought to room temperature and filtered to removeinsolubles, and then the filtrate was subjected to vacuum concentration.Chloroform (200 ml) and water (100 ml) were added to the residue and theobtained mixture was caused liquid-liquid separation. The aqueous phasewas further extracted with chloroform (50 ml) twice. The organic phaseswere combined, dried over anhydrous magnesium sulfate and subjected tovacuum concentration. The residue was purified by silica gel columnchromatography (a n-hexane/chloroform system) to give 1.27 g of thetitle compound (yield 69%).

EXAMPLE 124

Synthesis of2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

Toluene (30 ml) was mixed with 3.0 g (6.3 mmol) of2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5b]pyridine,10% Pd--C (100 mg) and 9.6 g (95 mmol) of triethylamine, followed by thedropwise addition of 2.9 g (63 mmol) of formic acid under stirring. Theobtained mixture was heated under reflux for 10 hours. The reactionliquid was brought to room temperature, and filtered to remove thecatalyst, and then the filtrate was subjected to vacuum concentration.Chloroform (100 ml) and water (100 ml) were added to the residue and theobtained mixture was caused liquid-liquid separation. The aqueous phasewas further extracted with chloroform (50 ml) twice. The organic phaseswere combined, dried over anhydrous magnesium sulfate and subjected tovacuum concentration. The residue was purified by silica gel columnchromatography (a n-hexane/ethyl acetate system) to give 2.3 g of thetitle compound (yield 92%).

EXAMPLE 125

Synthesis of 2-cyclopropyl -3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

Toluene (50 ml) was mixed with 2.0 g (4.0 mmol) of3-cyclopropanecarboxamido-2-[N-(2'-methoxycarbonylbiphenyl-4-yl)methyl]amino-5-bromo-4-methylpyridine,10% Pd--C (100 mg) and 6.1 g (60 mmol) of triethylamine, followed byheating under reflux with stirring. 2.0 g (43 mmol) of formic acid wasdropwise added thereto, followed by heating under reflux for 7 hours.The reaction liquid,was brought to room temperature and filtered toremove the catalyst, and then the filtrate was subjected to vacuumconcentration. Chloroform (100 ml) and water (100 ml) were added to theresidue and the obtained mixture was caused liquid-liquid separation.The aqueous phase was further extracted with chloroform (50 ml) twice.The organic phases were combined, dried over anhydrous magnesium sulfateand subjected to vacuum concentration. The residue was purified bysilica gel column chromatography (a n-hexane/chloroform system) to give1.45 g of the title compound (yield 90%).

EXAMPLE 201

Synthesis of 2-valerylamino-5-bromo-4-methyl-3-nitropyridine ##STR92##

A mixture comprising 10 g (43.1 mmol) of2-amino-5-bromo-4-methyl-3-nitropyridine and 6.8 g of pyridine washeated to 110° C. in a nitrogen atmosphere. 5.7 g (47.4 mmol) ofvaleroyl chloride was dropwise added thereto and the mixture was stirredat 110° C. for 5 hours. The reaction mixture was brought to roomtemperature, followed by the addition of methylene chloride (50 ml) andwater (50 ml). The organic phase was separated. The aqueous phase wasfurther extracted with methylene chloride (50 ml). The organic phaseswere combined, dried over anhydrous magnesium sulfate and subjected tovacuum concentration to give a crude crystal. It was recrystallized fromethyl acetate to give 11 g of2-valerylamino-5-bromo-4-methyl-3-nitropyridine (yield 81%).

m.p.; 134°˜135° C.

¹ NMR (400 MHz, CDCl₃); δ (ppm) 0.94 (3H, t, J=7.4 Hz), 1.35˜1.44 (2H,m), 1.65˜1.73 (2H, m), 2.45 (2H, t, J=7.5 Hz), 2.52 (3H, s), 7.97 (1H,br-s), 8.58 (1H, s)

FAB-MS; 316, 318 (MH⁺)

EXAMPLE 202

Synthesis of 2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-5-bromo-4-methyl-3-nitropyridine ##STR93##

4.0 g (13 mmol) of 5-bromo-4-methyl-3-nitro-2-valerylaminopyridine wasadded to a solution of 1.7 g (15 mmol) of potassium-t-butoxide intetrahydrofuran (30 ml), followed by stirring at room temperature for 45minutes. Then, this solution was heated, followed by the dropwiseaddition of a solution of 4.1 g (15 mmol) of2-(4'-bromomethylphenyl)benzonitrile in tetrahydrofuran (30 ml) underreflux. After the completion of the dropwise addition, the obtainedmixture was stirred for 3 hours. The reaction mixture was brought toroom temperature, followed by the addition of ethyl acetate (50 ml) anda saturated aqueous solution of ammonium chloride (100 ml) to conductextraction. The aqueous phase was further extracted with ethyl acetate(50 ml) twice. The organic phases were combined, dried over anhydrousmagnesium sulfate and concentrated. The residue of the concentration waspurified by silica gel column chromatography (ethyl acetate/n-hexane) togive 3.5 g of2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-5-bromo-4-methyl-3-nitropyridine(yield 55%).

¹ NMR (600 MHz, CDCl₃); δ (ppm) 0.86 (3H, t, J=7.4 Hz), 1.23˜1.32 (2H,m), 1.58˜1.67 (2H, m), 2.11 (2H, br), 2.46 (3H, s), 5.18 (2H, br),7.26˜7.76 (8H, m), 8.68 (1H, br-s)

FAB-MS; 507, 509 (MH⁺)

Example 203

Synthesis of2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine##STR94##

2.0 g (6.7 mmol) of2-cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine was added toa solution of 0.9 g (8.0 mmol) of potassium-t-butoxide intetrahydrofuran (35 ml), followed by stirring at room temperature forone hour. Then, this solution was heated, followed by the dropwiseaddition of a solution of 2.2 g (8.0 mmol) of2-(4'-bromomethylphenyl)benzonitrile in tetrahydrofuran (10 ml) underreflux. After the completion of the dropwise addition, the obtainedmixture was stirred for 3 hours. The reaction mixture was brought toroom temperature, followed by the addition of ethyl acetate (50 ml) anda saturated aqueous solution of ammonium chloride (50 ml) to conductextraction. The aqueous phase was further extracted with ethyl acetate(50 ml) once and with chloroform (50 ml) once. The organic phases werecombined, dried over anhydrous magnesium sulfate and subjected to vacuumconcentration. The residue was purified by silica gel columnchromatography (ethyl acetate/n-hexane) to give 2.1 g of2-[N-(2'-cyano-biphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine(yield 64%).

¹ NMR (600 MHz, CDCl₃); δ (ppm) 0.7˜0.9 (2H, br), 1.0˜1.1 (2H, br),1.52˜1.54 (1H, br), 2.44 (3H, s), 4.8˜5.6 (2H, br), 7.3˜7.6 (4H, br),7.41 (1H, t, J=7.7 Hz), 7.48 (1H, d, J=7.7 Hz), 7.61 (1H, t, J=7.7 Hz),7.73 (1H, d, J=7.7 Hz), 8.68 (1H, s)

FAB-MS 491, 493 (MH⁺)

EXAMPLE 204

Synthesis of2-butyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine##STR95##

Toluene (150 ml) was added to 5.0 g (9.9 mmol) of2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-5-bromo-4-methyl-3-nitropyridine,10% Pd--C (500 mg), 9.0 g (89 mmol) of triethylamine and 2.1 g (46 mmol)of formic acid. The obtained mixture was stirred and heated under refluxfor 11 hours. After the reaction liquid was brought to room temperatureand filtered to remove the catalyst, vacuum concentration was effected.Chloroform (200 ml) and water (200 ml) were added to the residue and theobtained mixture was caused liquid-liquid separation. The aqueous phasewas further extracted with chloroform (200 ml) once. The organic phaseswere combined, dried over anhydrous magnesium sulfate and subjected tovacuum concentration. The residue was purified by silica gel columnchromatography (n-hexane/chloroform) to give 2.7 g of2-butyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine(yield 72%).

¹ NMR (600 MHz, CDCl₃); δ (ppm) 0.91 (3H, J=7.3 Hz), 1.37˜1.46 (2H, m),1.71˜1.78 (2H, m), 2.70 (3H, d, J=0.6 Hz), 2.86 (2H, t, J=7.5 Hz), 5.56(2H, s), 7.04 (1H, dd, J=4.9, 0.6 Hz), 7.24 (2H, d, J=8.4 Hz), 7.41˜7.48(2H, m), 7.49 (2H, d, J=8.4 Hz), 7.64˜7.70 (1H, m), 7.74˜7.76 (1H, m),8.21 (1H, d, J=4.9 Hz)

FAB-MS; 381 (MH⁺)

EXAMPLE 205

Synthesis of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine ##STR96##

Toluene (200 ml) was added to 5.0 g (10 mmol) of2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine, 10% Pd--C (500 mg), 26 g(257 mmol) of triethylamine and 10 g (217 mmol) of formic acid. Theobtained mixture was stirred and heated under reflux for 7 hours. Afterthe reaction liquid was brought to room temperature and filtered toremove the catalyst, vacuum concentration was effected. Chloroform (200ml) and water (200 ml) were added to the residue and the obtainedmixture was caused liquid-liquid separation. The aqueous phase wasfurther extracted with chloroform (200 ml) once. The organic phases werecombined, dried over anhydrous magnesium sulfate and subjected to vacuumconcentration. The residue was purified by silica gel columnchromatography (n-hexane/chloroform) to give 2.8 g of2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine(yield 75%).

¹ NMR (600 MHz, CDCl₃); δ (ppm) 1.03˜1.08 (2H, m), 1.20˜1.25 (2H, m),1.93˜1.99 (1H, m), 2.65 (3H, s), 5.66 (2H, s), 7.00 (1H, d, J=5.0 Hz),7.31 (2H, d, J=8.5 Hz), 7.41˜7.48 (2H, m), 7.50 (2H, d, J=8.5 Hz),7.60˜7.64 (1H, m), 7.74˜7.76 (1H, m), 8.19 (1H, d, J=5.0 Hz)

FAB-MS; 365 (MH⁺)

EXAMPLE 206

Synthesis of2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-4-methyl-3-nitropyridine##STR97##

Toluene (150 ml) was added to 5.0 g (9.9 mmol) of2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-5-bromo-4-methyl-3-nitropyridine,10% Pd--C (500 mg) and 3.0 g (30 mmol) of triethylamine, followed byheating under reflux. 700 mg (15 mmol) of formic acid was dropwise addedthereto, followed by stirring for 6 hours. After the reaction liquid wasbrought to room temperature and filtered to remove the catalyst, vacuumconcentration was effected. Chloroform (200 ml) and water (200 ml) wereadded to the residue and the obtained mixture was caused liquid-liquidseparation. The aqueous phase was further extracted with chloroform (200ml) once. The organic phases were combined, dried over anhydrousmagnesium sulfate and subjected to vacuum concentration. The residue waspurified by silica gel column chromatography (n-hexane/chloroform) togive 3.5 g of2-[N-(2'-cyanobiphenyl-4-yl)methyl]valerylamino-4-methyl-3-nitropyridine(yield 83%).

¹ NMR (600 MHz, CDCl₃); δ (ppm) 0.82 (3H, t, J=7.4 Hz), 1.23˜1.27 (2H,m), 1.58˜1.68 (2H, m), 2.09 (2H, br), 2.39 (3H, s), 5.20 (2H, br),7.21˜7.74 (9H, m), 8.45 (1H, br-s)

FAB-MS; 429 (MH⁺)

EXAMPLE 207

Synthesis of2-(2'-cyanobiphenyl-4-yl)methylamino-3-cyclopropanecarboxamido-5-bromo-4-methylpyridine##STR98##

Methanol (50 ml) was added to 3.0 g (6.1 mmol) of2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine,8.6 g (172 mmol) of hydrazine monohydrate, activated carbon (300 mg) and9.6 g (35.5 mmol) of ferric chloride hexahydrate, followed by heatingunder reflux for 25 hours. After the reaction liquid was brought to roomtemperature and filtered to remove insolubles, vacuum concentration waseffected. Chloroform (50 ml) and water (50 ml) were added to the residueand the obtained mixture was caused liquid-liquid separation. Theaqueous phase was further extracted with chloroform (20 ml) twice. Theorganic phases were combined, dried over anhydrous sodium sulfate andsubjected to vacuum concentration. The residue was purified by silicagel chromatography (n-hexane/ethyl acetate) to give 1.3 g of2-(2'-cyanobiphenyl-4-yl)methylamino-3-cyclopropanecarboxamido-5-bromo-4-methylpyridine(yield 46%).

¹ NMR (600 MHz, CDCl₃); δ (ppm) 0.85˜0.92 (2H, m), 1.00˜1.08 (2H, m),1.77˜1.86 (1H, m), 2.27 (3H, s), 4.70 (2H, s), 6.00 (1H, br-s), 7.41(1H, ddd, J=7.7, 7.7, 1.5 Hz), 7.43 (2H, d, J=8.3 Hz), 7.47 (1H, dd,J=7.7, 1.5 Hz), 7.48 (2H, d, J=8.3 Hz), 7.62 (1H, ddd, J=7.7, 7.7, 1.5Hz), 7.72 (1H, dd, J=7.7, 1.5 Hz), 8.05 (1H, br-s), 8.19 (1H, s)

FAB-MS; 461, 463 (MH⁺)

EXAMPLE 208

Synthesis of2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

Toluene (30 ml) was added to 2.0 g (4.3 mmol) of2-(2'-cyanobiphenyl-4-yl)methylamino-3-cyclopropanecarboxamide-5-bromo-4-methyl-pyridine,1.0 g (21.7 mmol) of formic acid, 3.5 g (34.6 mmol) of triethylamine and10% Pd--C (300 mg), followed by heating under reflux for 6 hours. Afterthe reaction liquid was brought to room temperature and filtered toremove the catalyst, vacuum concentration was effected. Chloroform (100ml) and water (50 ml) were added to the residue and the obtained mixturewas caused liquid-liquid separation. The aqueous phase was furtherextracted with chloroform (50 ml) twice. The organic phases werecombined, dried over anhydrous magnesium sulfate and subjected to vacuumconcentration. The residue was purified by silica gel columnchromatography (n-hexane/ethyl acetate) to give 1.3 g of2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine(yield 82%).

EXAMPLE 209

Synthesis of2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine##STR99##

Ethanol (50 ml) was added to 3.0 g (6.1 mmol) of2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-5-bromo-4-methyl-3-nitropyridine,3.0 g of powdered iron and acetic acid (10 ml), followed by stirringunder heating at 80° C. for one hour. After the reaction liquid wasbrought to room temperature and filtered to remove the catalyst, vacuumconcentration was effected. Chloroform (100 ml) and water (50 ml) wereadded to the residue and the obtained mixture was caused liquid-liquidseparation. The aqueous phase was further extracted with chloroform (50ml). After the organic phases were combined and washed with an aqueoussolution (100 ml) of sodium hydrogencarbonate, the resultant organicphase was dried over anhydrous magnesium sulfate and subjected to vacuumconcentration. The residue was purified by silica gel columnchromatography (n-hexane/chloroform) to give 1.8 g of2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)-methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine(yield 67%).

¹ NMR (600 MHz, CDCl₃); δ (ppm) 1.02˜1.13 (2H, m), 1.21˜1.28 (2H, m),1.92˜2.00 (1H, m), 2.66 (3H, s), 5.61 (2H, s), 7.30 (2H, d, J=8.0 Hz),7.42 (1H, ddd, J=7.5, 7.5, 1.2 Hz), 7.45 (1H, dd, J=7.5, 1.2 Hz), 7.49(2H, d, J=8.0 Hz), 7.62 (1H, ddd, J=7.5, 7.5, 1.2 Hz), 7.74 (1H, dd,J=7.5, 1.2 Hz), 8.35 (1H, s) FAB-MS; 443, 445 (MH⁺)

Example 210

Synthesis of 2-cyclopropyl-3-(2'-cyano-biphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine

Toluene (20 ml) was added to 2.0 g (4.3 mmol) of2-(2'-cyanobiphenyl-4-yl)methylamino-3-cyclopropane-carboxamido-5-bromo-4-methylpyridine,p-toluene sulfonic acid monohydrate (200 mg) and Molecular Sieves 4A(500 mg), followed by heating under reflux with stirring for 3 hours.The reaction solution was brought to room temperature and filteredthrough Celite to remove insolubles. Chloroform (100 ml) and an aqueoussolution (100 ml) of sodium hydrogen-carbonate were added to thefiltrate and the obtained mixture was caused liquid-liquid separation.The aqueous phase was further extracted with chloroform (50 ml) twice.The organic phases were combined, dried over anhydrous magnesium sulfateand subjected to vacuum concentration. The residue was purified bysilica gel column chromatography (n-hexane/ethyl acetate) to give 1.7 gof2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine(yield 88%).

EXAMPLE 211

Synthesis of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

Toluene (30 ml) was added to 2.0 g (4.5 mmol) of2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine,1.24 g (27.0 mmol) of formic acid, 4.55 g (45.0 mmol) of triethylamineand 10% Pd--C (100 mg), followed by heating under reflux for 6 hours.After the reaction liquid was brought to room temperature and filteredto remove the catalyst, vacuum concentration was effected. Chloroform(50 ml) and water (50 ml) were added to the residue and the obtainedmixture was caused liquid-liquid separation. The aqueous phase wasfurther extracted with chloroform (30 ml) twice. The organic phases werecombined, dried over anhydrous magnesium sulfate and subjected to vacuumconcentration. The residue was purified by silica gel columnchromatography (n-hexane/ethyl acetate) to give 1.28 g of2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine(yield 78%).

EXAMPLE 212

Synthesis of 2-cyclopropyl -3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

Toluene (50 ml) was added to 4.0 g (9.7 mmol) of2-[N-(2'-cyanobiphenyl-4-yl)methyl]cyclopropanecarboxamido-4-methyl-3-nitropyridine,4.5 g (97.8 mmol) of formic acid, 14.7 g (145.5 mmol) of triethylamineand 10% Pd--C (200 mg), followed by heating under reflux for 15 hours.After the reaction liquid was brought to room temperature and filteredto remove the catalyst, vacuum concentration was effected. Chloroform(100 ml) and water (100 ml) were added to the residue and the obtainedmixture was caused liquid-liquid separation. The aqueous phase wasfurther extracted with chloroform (50 ml) twice. The organic phases werecombined, dried over anhydrous magnesium sulfate and subjected to vacuumconcentration. The residue was purified by silica gel columnchromatography (n-hexane/ethyl acetate) to give 2.9 g of2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine(yield 83%).

Next, Referential Examples, wherein an objective compound is preparedfrom the 2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivatives (II) which has been prepared by the use of an activebiphenyl derivative (IV) according to the present invention as asynthesis intermediate, in the production of2-alkyl-3-(2'-alkoxycarbonylbiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivatives which are antagonists against angiotensin II receptor andare useful as an antihypertensive drug or a remedy for hemal lesions,will be given.

REFERENTIAL EXAMPLES Referential Example 1

Synthesis of 2-cyclopropyl -3 -(2'-carboxybiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine ##STR100##

Ethanol (40 ml) and a 10% aqueous solution (20 ml) of sodium hydroxidewere added to 1.32 g (3.3 mmol) of2-cyclopropyl-3-(2'-methoxycarbonylbiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine,followed by heating under reflux for 2 hours. After the reaction liquidwas cooled, it was concentrated to about one-half the initial volume,and neutralized with 2N hydrochloric acid and acetic acid. The crystalthus precipitated was recovered by filtration and recrystallized fromaqueous ethanol to give 1.03 g of the title compound (yield 81%).

¹ H-NMR (600 MHz, DMSO-d₆); δ (ppm) 1.06 (4H, m), 2.27 (1H, tt, J=8.0,5.0 Hz), 2.50 (3H, s), 5.63 (2H, s), 7.04 (1H, d, J=5.0 Hz), 7.27 (4H,m), 7.33 (1H, dd, J=8.0, 1.0 Hz), 7.43 (1H, ddd, J=8.0, 8.0, 1.0 Hz),7.54 (1H, ddd, J=8.0, 8.0, 2.0 Hz), 7.70 (1H, dd, J=8.0, 2.0 Hz), 8.13(1H, d, J=5.0 Hz), 12.70 (1H, br-s)

Referential Example 2

Synthesis of 2-cyclopropyl -3-(2'-carboxybiphenyl-4-yl)methyl-7-methyl-3H-imidazo-[4,5-b]pyridine

2.7 g (6.2 mmol) of2-cyclopropyl-3-[2'-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-7-methyl3H-imidazo[4,5-b]pyridinewas dissolved in ethanol (50 ml), followed by the addition of 4Nhydrochloric acid (25 ml). The obtained mixture was heated under refluxfor 9 hours. The reaction liquid was cooled and added to a saturatedaqueous solution of sodium hydrogencarbonate, followed by the extractionwith chloroform. After washing with water and drying, vacuumconcentration was conducted. The residue was dissolved in ethanol (25ml), followed by the addition of a 2N aqueous solution (25 ml) of sodiumhydroxide. The obtained mixture was heated under reflux for 6 hours. Thereaction liquid was concentrated to dryness, and then water was addedthereto to dissolve the residue. Then, the solution obtained wasneutralized with 2N hydrochloric acid and acetic acid. The crystal thusprecipitated was recovered by filtration and recrystallized from aqueousethanol to give 1.92 g of the title compound (yield 81%).

Referential Example 3

Synthesis of 2-cyclopropyl-3-(2'-carboxybiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine

Water (8.7 ml) and 5.3 g of sulfuric acid were added to 5.0 g (11.5mmol) of2-cyclopropyl-3-[2-(4",4"-dimethyloxazolin-2"-yl)biphenyl-4-yl]methyl-7-methyl-3H-imidazo[4,5-b]pyridine,followed by heating under reflux for 36 hours. The pH of the reactionmixture was adjusted to 6 with a 10% aqueous solution of sodiumhydroxide and acetic acid. The crystal thus precipitated was recoveredby filtration and recrystallized from aqueous ethanol to give 3.74 g ofthe title compound (yield 85%).

We claim:
 1. A process for the preparation of a2-substituted-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]-pyridinederivative (II) represented by the following formula: ##STR101## whereinR², R³ and R⁴ are each as follows, characterized by conductingcyclization and dehalogenation of a2-[N-(biphenyl-4-yl)methyl]alcylamino-3-nitropyridine or a2-[N-(biphenyl-4-yl)methyl]alkoxycarbonylamino-3-nitropyridinederivative (I) represented by the following formula under reducingconditions: ##STR102## wherein R¹ represents a halogen atom, and furtherthe halogen atom represents a bromine atom or a chlorine atom; R²represents a hydrogen atom or a methyl group; R³ represents a cycloalkylgroup, a lower alkyl group or a lower alkoxy group; and R⁴ represents agroup represented by the following general formula:

    --COOR.sup.5

wherein R⁵ represents a lower alkyl group, a cycloalkyl group, analkoxyalkyl group, a thioalkoxyalkyl group, a cycloether group, an arylgroup, an aralkyl group, an alkenyl group, an alkynyl group or atrialkylsilyl group or R⁴ is a group represented by the followingformula: ##STR103##
 2. A process for the preparation of a 2-substituted-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]-pyridine derivative (II)according to claim 1, characterized by reacting a 2-acylamino or2-alkoxycarbonylamino-3-nitropyridine derivative (III) represented bythe following formula: ##STR104## wherein R¹, R² and R³ are each asdefined above, with an active biphenyl derivative (IV) represented bythe following general formula: ##STR105## wherein Y represents a leavinggroup in the course of organic synthesis; and R⁴ is as defined above, toform a 2-[N-(biphenyl-4-yl)methyl]acylamino-3-nitropyridine or a2-[N-(biphenyl-4-yl)methyl]alkoxycarbonylamino-3-nitropyridinederivative (I) through N-alkylation, and then conducting the cyclizationand dehalogenation thereof under reducing conditions.
 3. A process forthe preparation of a 2-substituted-3-(biphenyl-4yl) methyl-3H-imidazo[4,5-b]-pyridine derivative (II) according to claim 1, characterized byreacting a 2-amino-3-nitropyridine derivative (V) represented by thefollowing formula: ##STR106## wherein R¹ and R.sup. 2 are each asdefined above, with a compound represented by the general formula:

    R.sup.3 COZ or (R.sup.3 CO).sub.2 O

wherein Z represents a leaving group in the course of organic synthesis;and R³ is as defined above, to form a 2-acylamino-3-nitropyridine or2-alkoxycarbonylamino-3-nitropyridine derivative (III), reacting it withan active biphenyl derivative (IV) to form a2-N-(biphenyl-4-yl)methyl]acylamino-3-nitropyridine or 2-[N-(biphenyl-4-yl) methyl]alkoxycarbonylamino-3-nitropyridine derivative (I) throughN-alkylation, and then conducting the cyclization or the cyclization anddehalogenation thereof under reducing conditions.
 4. The process for thepreparation of a 2-substituted-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5-b]-pyridine derivative (II) asset forth in any of claims 1 to 3, wherein the catalyst and/or reducingagent to be used in the reduction is one selected among a combination ofa palladium-carbon catalyst with an amine and an organic acid, acombination of a palladium-carbon catalyst with hydrogen, a combinationof sodium borohydride with cupric chloride, a combination of apalladium-carbon catalyst with sodium hypophosphite and a combination ofa palladium-carbon catalyst with iron and acetic acid.
 5. A process forthe preparation of a2-alkyl-3-(biphenyl-4-yl)methyl-3H-imidazo[4,5]-pyridine derivative (II)according to claim 1, characterized by conducting the reductivecyclization of a 2-[N-(biphenyl-4-yl)methyl]alkylamido-3-nitropyridinederivative (I) with triethylamine and formic acid or triethylamine andacetic acid as reducing agents in the presence of a palladium-carboncatalyst.
 6. A process for the preparation of a 2-substituted3-(2'-cyanobiphenyl-4-yl) methyl-3H-imidazo[4,5-b]-pyridine derivative(II) represented by the following formula: ##STR107## wherein R¹represents a hydrogen atom or a methyl group; and R² represents acycloalkyl group, a lower alkyl group or a lower alkoxy groupcharacterized by conducting the cyclization and dehalogenation of a2-[N-(2'-cyanobiphenyl-4-yl)-methyl]acylamino-5-halogeno-3-nitropyridineor2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkoxycarbonylamino-5-halogeno-3-nitropyridinederivative (I) represented by the following formula under reducingconditions: ##STR108## wherein R¹ represents a hydrogen atom or a methylgroup; X represents a halogen atom, R² represents a cycloalkyl group, alower alkyl group or a lower alkoxy group, and further the halogen atomrepresents a bromine atom or a chlorine atom.
 7. A process for thepreparation of a2-substituted-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II) according to claim 6, characterized by reacting a2-substituted-amido-5-halogeno-3-nitropyridine derivative (III)represented by the following formula: ##STR109## wherein R¹ R² and X areeach as defined in claim 6, with an active biphenyl derivative (IV)represented by the following formula: ##STR110## wherein Y represents aleaving group in the course of organic synthesis, to form a2-[N-(2'-cyanobiphenyl-4-yl)methyl]acylamino-5-halogeno-3-nitropyridineor2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkoxycarbonylamino-5-halogeno-3-nitropyridinederivative (I) through N-alkylation, and then conducting the cyclizationand dehalogenation thereof under reducing conditions.
 8. A process forthe preparation of a2-substituted-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo-[4,5-b]pyridinederivative (II) according to claim 6, characterized by reacting a2-amino-5-halogeno-3-nitropyridine derivative (V) represented by thefollowing formula: ##STR111## wherein R¹ and X are each as defined inclaim 6, with a compound represented by the formula:

    R.sup.2 COZ or (R.sup.2 CO).sub.2 O

wherein Z represents a leaving group in the course of organic synthesis;and R² is as defined above, to form a2-acylamino-5-halogeno-3-nitropyridine or2-alkoxycarbonylamino-5-halogeno-3-nitropyridine derivative (III),reacting it with an active biphenyl derivative (IV) to form a2-[N-(2'-cyanobiphenyl-4-yl)methyl][alkylamido]acylamino-5-halogeno-3-nitropyridineor2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkoxycarbonylamino-5-halogeno-3-nitropyridinederivative (I) through N-alkylation, and then conducting the cyclizationand dehalogenation thereof under reducing conditions.
 9. The process forthe preparation of a2-substituted-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[4,5-b]pyridinederivative (II) as set forth in any of claims 6 to 8, wherein thecatalyst and/or reducing agent to be used in the reduction is oneselected from among a combination of a palladium-carbon catalyst with anamine and an organic acid, a combination of a palladium-carbon catalystwith hydrogen, a combination of sodium borohydride with cupric chloride,a combination of a palladium-carbon catalyst With sodium hypophosphiteand a combination of a palladium-carbon catalyst with iron and aceticacid.
 10. A process for the preparation of a2-substituted-3-(2'-cyanobiphenyl-4-yl)methyl-3H-imidazo[-4,5-b]pyridinederivative (II)according to claim 6, characterized by conducting thecyclization and dehalogenation of a2-[N-(2'-cyanobiphenyl-4-yl)methyl]acylamino-5-halogeno-3-nitropyridineor2-[N-(2'-cyanobiphenyl-4-yl)methyl]alkoxycarbonylamino-5-halogeno-3-nitropyridinederivative (I) by the use of triethylamine and formic acid ortriethylamine and acetic acid as reducing agents in the presence of apalladium-carbon catalyst under reducing conditions.